rs55758736

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001715.3(BLK):c.211G>A(p.Ala71Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,613,932 control chromosomes in the GnomAD database, including 156 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 21 hom., cov: 32)

Exomes 𝑓: 0.011 ( 135 hom. )

Consequence

BLK
NM_001715.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:15

Conservation

PhyloP100: 0.860

Publications

45 publications found

Variant links:

Genes affected

BLK (HGNC:1057): (BLK proto-oncogene, Src family tyrosine kinase) This gene encodes a nonreceptor tyrosine-kinase of the src family of proto-oncogenes that are typically involved in cell proliferation and differentiation. The protein has a role in B-cell receptor signaling and B-cell development. The protein also stimulates insulin synthesis and secretion in response to glucose and enhances the expression of several pancreatic beta-cell transcription factors. [provided by RefSeq, Aug 2010]

BLK Gene-Disease associations (from GenCC):

maturity-onset diabetes of the young
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
systemic lupus erythematosus
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet
maturity-onset diabetes of the young type 11
Inheritance: AD, Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
monogenic diabetes
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

BLK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042304844).

BP6

Variant 8-11548067-G-A is Benign according to our data. Variant chr8-11548067-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 12319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0143 (2182/152200) while in subpopulation AFR AF = 0.0234 (971/41520). AF 95% confidence interval is 0.0222. There are 21 homozygotes in GnomAd4. There are 1055 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2182 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLK	NM_001715.3 link	c.211G>A	p.Ala71Thr	missense_variant	Exon 4 of 13	ENST00000259089.9	NP_001706.2	P51451Q05D26

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BLK	ENST00000259089.9 link	c.211G>A	p.Ala71Thr	missense_variant	Exon 4 of 13	1	NM_001715.3	ENSP00000259089.4	P51451
BLK	ENST00000533828.1 link	n.409G>A		non_coding_transcript_exon_variant	Exon 2 of 3	4
BLK	ENST00000645242.1 link	n.362G>A		non_coding_transcript_exon_variant	Exon 3 of 12
BLK	ENST00000696154.2 link	n.362G>A		non_coding_transcript_exon_variant	Exon 3 of 12				A0A8Q3SIE3

Frequencies

GnomAD3 genomes

AF:

0.0143

AC:

2181

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0234

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0138

Gnomad ASJ

AF:

0.0386

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.0114

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.0116

AC:

2907

AN:

251454

AF XY:

0.0111

show subpopulations

Gnomad AFR exome

AF:

0.0242

Gnomad AMR exome

AF:

0.00978

Gnomad ASJ exome

AF:

0.0405

Gnomad EAS exome

AF:

0.000217

Gnomad FIN exome

AF:

0.00222

Gnomad NFE exome

AF:

0.0123

Gnomad OTH exome

AF:

0.0176

GnomAD4 exome

AF:

0.0111

AC:

16258

AN:

1461732

Hom.:

135

Cov.:

AF XY:

0.0112

AC XY:

8150

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.0266

AC:

889

AN:

33474

American (AMR)

AF:

0.00984

AC:

440

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0393

AC:

1028

AN:

26130

East Asian (EAS)

AF:

0.000176

AC:

AN:

39700

South Asian (SAS)

AF:

0.00682

AC:

588

AN:

86246

European-Finnish (FIN)

AF:

0.00236

AC:

126

AN:

53414

Middle Eastern (MID)

AF:

0.0494

AC:

282

AN:

5714

European-Non Finnish (NFE)

AF:

0.0108

AC:

12046

AN:

1111952

Other (OTH)

AF:

0.0141

AC:

852

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

891

1783

2674

3566

4457

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

444

888

1332

1776

2220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0143

AC:

2182

AN:

152200

Hom.:

Cov.:

AF XY:

0.0142

AC XY:

1055

AN XY:

74420

show subpopulations

African (AFR)

AF:

0.0234

AC:

971

AN:

41520

American (AMR)

AF:

0.0137

AC:

210

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0386

AC:

134

AN:

3468

East Asian (EAS)

AF:

0.000772

AC:

AN:

5180

South Asian (SAS)

AF:

0.00436

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0114

AC:

776

AN:

68008

Other (OTH)

AF:

0.0175

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

106

213

319

426

532

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0134

Hom.:

Bravo

AF:

0.0156

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.0119

AC:

ESP6500AA

AF:

0.0216

AC:

ESP6500EA

AF:

0.0121

AC:

104

ExAC

AF:

0.0117

AC:

1421

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0162

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Maturity-onset diabetes of the young type 11

Pathogenic:1Benign:4

Aug 25, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2024

Molecular Genetics, Royal Melbourne Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Oct 05, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:5

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 23, 2013

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 25, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 22696686, 20981092, 26821283, 23261300, 22995991, 25333069, 19667185, 23224494, 27884173, 31101814, 32028929) -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BLK: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Monogenic diabetes

Benign:2

Apr 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Mar 03, 2017

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

ACMG Criteria:BP4 (6 predictors), PP3 (4 predictors), BS1 (2.5% in African 1.6% in European in 1000g), BS2 (about equal cases and controls in type2diabetesgenetics.org), PS3 (functional studies show effect) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.21

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.22

LIST_S2

Uncertain

0.89

MetaRNN

Benign

0.042

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.5

PhyloP100

0.86

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.1

REVEL

Benign

0.16

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.56

Vest4

0.096

MPC

0.039

ClinPred

0.013

GERP RS

3.4

Varity_R

0.079

gMVP

0.34

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over