8-11556728-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001715.3(BLK):c.843T>C(p.Phe281=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.839 in 1,614,022 control chromosomes in the GnomAD database, including 569,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50797 hom., cov: 32)
  • Exomes 𝑓: 0.84 (519043 hom.)
• Consequence: BLK NM_001715.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.35

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 8-11556728-T-C is Benign according to our data. Variant chr8-11556728-T-C is described in ClinVar as [Benign]. Clinvar id is 128529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11556728-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLK	NM_001715.3	c.843T>C	p.Phe281=	synonymous_variant	9/13	ENST00000259089.9
LOC105379241	XR_948956.3	n.377-67A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLK	ENST00000259089.9	c.843T>C	p.Phe281=	synonymous_variant	9/13	1	NM_001715.3	P1
	ENST00000602626.2	n.331-67A>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.814 AC: 123807 AN: 152030 Hom.: 50751 Cov.: 32

Gnomad AFR AF: 0.731

Gnomad AMI AF: 0.895

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.887

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.778

Gnomad FIN AF: 0.804

Gnomad MID AF: 0.791

Gnomad NFE AF: 0.844

Gnomad OTH AF: 0.832

GnomAD3 exomes AF: 0.837 AC: 210438 AN: 251478 Hom.: 88421 AF XY: 0.835 AC XY: 113485 AN XY: 135914

Gnomad AFR exome AF: 0.737

Gnomad AMR exome AF: 0.863

Gnomad ASJ exome AF: 0.883

Gnomad EAS exome AF: 0.951

Gnomad SAS exome AF: 0.773

Gnomad FIN exome AF: 0.811

Gnomad NFE exome AF: 0.842

Gnomad OTH exome AF: 0.850

GnomAD4 exome AF: 0.842 AC: 1230750 AN: 1461874 Hom.: 519043 Cov.: 72 AF XY: 0.840 AC XY: 611068 AN XY: 727242

Gnomad4 AFR exome AF: 0.733

Gnomad4 AMR exome AF: 0.865

Gnomad4 ASJ exome AF: 0.881

Gnomad4 EAS exome AF: 0.943

Gnomad4 SAS exome AF: 0.776

Gnomad4 FIN exome AF: 0.812

Gnomad4 NFE exome AF: 0.846

Gnomad4 OTH exome AF: 0.848

GnomAD4 genome AF: 0.814 AC: 123908 AN: 152148 Hom.: 50797 Cov.: 32 AF XY: 0.813 AC XY: 60459 AN XY: 74386

Gnomad4 AFR AF: 0.731

Gnomad4 AMR AF: 0.859

Gnomad4 ASJ AF: 0.887

Gnomad4 EAS AF: 0.949

Gnomad4 SAS AF: 0.778

Gnomad4 FIN AF: 0.804

Gnomad4 NFE AF: 0.844

Gnomad4 OTH AF: 0.835

Alfa AF: 0.832 Hom.: 45239

Bravo AF: 0.816

Asia WGS AF: 0.860 AC: 2989 AN: 3478

EpiCase AF: 0.838

EpiControl AF: 0.842

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2021	- -

Maturity-onset diabetes of the young type 11 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	9.1
Dann	Benign	0.68

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

Other links and lift over

dbSNP: rs2306234; hg19: chr8-11414237; COSMIC: COSV52054606; COSMIC: COSV52054606;