8-11556728-T-C

Variant names:

• chr8-11556728-T-C
• rs2306234
• NM_001715.3:c.843T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001715.3(BLK):​c.843T>C​(p.Phe281Phe) 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:8
• Conservation: PhyloP100: 1.35
• Publications: 30 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

BLK-AS1 (HGNC:58190):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001715.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLK	NM_001715.3	MANE Select	c.843T>C	p.Phe281Phe	synonymous	Exon 9 of 13	NP_001706.2
	BLK	NM_001330465.2		c.630T>C	p.Phe210Phe	synonymous	Exon 8 of 12	NP_001317394.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLK	ENST00000259089.9	TSL:1 MANE Select	c.843T>C	p.Phe281Phe	synonymous	Exon 9 of 13	ENSP00000259089.4
	BLK	ENST00000855155.1		c.843T>C	p.Phe281Phe	synonymous	Exon 9 of 13	ENSP00000525214.1
	BLK	ENST00000855156.1		c.843T>C	p.Phe281Phe	synonymous	Exon 8 of 12	ENSP00000525215.1

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

GnomAD2 exomes AF: 0.837 AC: 210438 AN: 251478 AF XY: 0.835

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 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

African (AFR) AF: 0.733 AC: 24528 AN: 33478

American (AMR) AF: 0.865 AC: 38700 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.881 AC: 23036 AN: 26136

East Asian (EAS) AF: 0.943 AC: 37424 AN: 39700

South Asian (SAS) AF: 0.776 AC: 66896 AN: 86258

European-Finnish (FIN) AF: 0.812 AC: 43359 AN: 53420

Middle Eastern (MID) AF: 0.842 AC: 4854 AN: 5766

European-Non Finnish (NFE) AF: 0.846 AC: 940738 AN: 1111996

Other (OTH) AF: 0.848 AC: 51215 AN: 60396

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

African (AFR) AF: 0.731 AC: 30332 AN: 41482

American (AMR) AF: 0.859 AC: 13139 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 3081 AN: 3472

East Asian (EAS) AF: 0.949 AC: 4904 AN: 5168

South Asian (SAS) AF: 0.778 AC: 3750 AN: 4818

European-Finnish (FIN) AF: 0.804 AC: 8506 AN: 10582

Middle Eastern (MID) AF: 0.793 AC: 233 AN: 294

European-Non Finnish (NFE) AF: 0.844 AC: 57384 AN: 68012

Other (OTH) AF: 0.835 AC: 1765 AN: 2114

Alfa AF: 0.833 Hom.: 48218

Bravo AF: 0.816

Asia WGS AF: 0.860 AC: 2989 AN: 3478

EpiCase AF: 0.838

EpiControl AF: 0.842

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Maturity-onset diabetes of the young type 11 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	9.1
DANN	Benign	0.68
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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