chr8-11543171-G-A

Variant names:

• chr8-11543171-G-A
• rs2245250
• NM_001715.3:c.-1-53G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001715.3(BLK):​c.-1-53G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.456 in 1,610,296 control chromosomes in the GnomAD database, including 176,966 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13810 hom., cov: 31)
  • Exomes 𝑓: 0.46 (163156 hom.)
• Consequence: BLK NM_001715.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.369
• Publications: 11 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-11543171-G-A is Benign according to our data. Variant chr8-11543171-G-A is described in ClinVar as [Benign]. Clinvar id is 1192423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLK	NM_001715.3	c.-1-53G>A		intron_variant	Intron 1 of 12	ENST00000259089.9	NP_001706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLK	ENST00000259089.9	c.-1-53G>A		intron_variant	Intron 1 of 12	1	NM_001715.3	ENSP00000259089.4
BLK	ENST00000645242.1	n.275-2881G>A		intron_variant	Intron 1 of 11
BLK	ENST00000696154.2	n.275-2881G>A		intron_variant	Intron 1 of 11

Frequencies

GnomAD3 genomes AF: 0.411 AC: 62361 AN: 151882 Hom.: 13808 Cov.: 31

Gnomad AFR AF: 0.359

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.568

Gnomad EAS AF: 0.00519

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.426

GnomAD4 exome AF: 0.460 AC: 671426 AN: 1458296 Hom.: 163156 AF XY: 0.458 AC XY: 332016 AN XY: 725480

African (AFR) AF: 0.355 AC: 11861 AN: 33432

American (AMR) AF: 0.245 AC: 10933 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 14685 AN: 26092

East Asian (EAS) AF: 0.00212 AC: 84 AN: 39648

South Asian (SAS) AF: 0.302 AC: 25985 AN: 86008

European-Finnish (FIN) AF: 0.405 AC: 20923 AN: 51648

Middle Eastern (MID) AF: 0.464 AC: 2658 AN: 5728

European-Non Finnish (NFE) AF: 0.502 AC: 557149 AN: 1110792

Other (OTH) AF: 0.450 AC: 27148 AN: 60308

GnomAD4 genome AF: 0.410 AC: 62367 AN: 152000 Hom.: 13810 Cov.: 31 AF XY: 0.397 AC XY: 29509 AN XY: 74302

African (AFR) AF: 0.358 AC: 14823 AN: 41412

American (AMR) AF: 0.324 AC: 4956 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.568 AC: 1970 AN: 3468

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5186

South Asian (SAS) AF: 0.291 AC: 1402 AN: 4810

European-Finnish (FIN) AF: 0.369 AC: 3903 AN: 10578

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.500 AC: 33945 AN: 67952

Other (OTH) AF: 0.422 AC: 891 AN: 2112

Alfa AF: 0.475 Hom.: 2210

Bravo AF: 0.400

Asia WGS AF: 0.164 AC: 574 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 17, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Maturity-onset diabetes of the young type 11 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Systemic lupus erythematosus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

BLK gene is associated with Systemic lupus erythematosus, sjogren's syndrome and other systemic inflammatory conditions. However no sufficient evidence is found to ascertain the role of this particular variant rs2245250, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.75
PhyloP100		-0.37
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2245250; hg19: chr8-11400680; COSMIC: COSV52057589; COSMIC: COSV52057589;