rs141865425

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001715.3(BLK):c.713G>A(p.Arg238Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00456 in 1,614,156 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R238W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 23 hom. )

Consequence

BLK
NM_001715.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:9

Conservation

PhyloP100: 5.59

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0119256675).

BP6

Variant 8-11555425-G-A is Benign according to our data. Variant chr8-11555425-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 210528.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11555425-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 455 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLK	NM_001715.3 linkuse as main transcript	c.713G>A	p.Arg238Gln	missense_variant	8/13	ENST00000259089.9
LOC105379241	XR_948956.3 linkuse as main transcript	n.1117+293C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLK	ENST00000259089.9 linkuse as main transcript	c.713G>A	p.Arg238Gln	missense_variant	8/13	1	NM_001715.3	P1
	ENST00000602626.2 linkuse as main transcript	n.622+293C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00299

AC:

455

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00442

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00462

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00307

AC:

773

AN:

251430

Hom.:

AF XY:

0.00328

AC XY:

446

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.00133

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00297

Gnomad FIN exome

AF:

0.00310

Gnomad NFE exome

AF:

0.00463

Gnomad OTH exome

AF:

0.00391

GnomAD4 exome

AF:

0.00473

AC:

6909

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00466

AC XY:

3391

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.000806

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00252

Gnomad4 FIN exome

AF:

0.00279

Gnomad4 NFE exome

AF:

0.00554

Gnomad4 OTH exome

AF:

0.00470

GnomAD4 genome

AF:

0.00299

AC:

455

AN:

152276

Hom.:

Cov.:

AF XY:

0.00317

AC XY:

236

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00190

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00442

Gnomad4 NFE

AF:

0.00462

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00443

Hom.:

Bravo

AF:

0.00276

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00325

AC:

395

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00403

EpiControl

AF:

0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2020	This variant is associated with the following publications: (PMID: 31101814, 28766502) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	ENSG00000269954: BS2 -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 24, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Maturity-onset diabetes of the young type 11

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 10, 2023	- -

Systemic lupus erythematosus

Pathogenic:1

Pathogenic, no assertion criteria provided

research

Carola Vinuesa Lab, John Curtin School of Medical Research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.18

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.12

T;T;T

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.039

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Benign

-0.84

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.47

Polyphen

1.0

.;D;.

Vest4

0.81, 0.74

MVP

0.81

MPC

0.16

ClinPred

0.089

GERP RS

3.6

Varity_R

0.37

gMVP

0.62

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over