8-11495032-T-C

Variant names:

• chr8-11495032-T-C
• rs2618476
• NM_001715.3:c.-2+441T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001715.3(BLK):​c.-2+441T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 152,176 control chromosomes in the GnomAD database, including 6,734 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (6734 hom., cov: 33)
• Consequence: BLK NM_001715.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46
• Publications: 74 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.694 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLK	NM_001715.3	MANE Select	c.-2+441T>C		intron	N/A	NP_001706.2
	BLK	NM_001330465.2		c.-91+441T>C		intron	N/A	NP_001317394.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLK	ENST00000259089.9	TSL:1 MANE Select	c.-2+441T>C		intron	N/A	ENSP00000259089.4
	BLK	ENST00000525389.1	TSL:1	n.423+441T>C		intron	N/A
	BLK	ENST00000645242.1		n.274+7865T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.265 AC: 40335 AN: 152058 Hom.: 6713 Cov.: 33

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.223

Gnomad AMR AF: 0.452

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.713

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.282

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.264

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.265 AC: 40370 AN: 152176 Hom.: 6734 Cov.: 33 AF XY: 0.273 AC XY: 20324 AN XY: 74400

African (AFR) AF: 0.141 AC: 5842 AN: 41550

American (AMR) AF: 0.453 AC: 6921 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 512 AN: 3468

East Asian (EAS) AF: 0.714 AC: 3685 AN: 5164

South Asian (SAS) AF: 0.352 AC: 1700 AN: 4826

European-Finnish (FIN) AF: 0.282 AC: 2989 AN: 10590

Middle Eastern (MID) AF: 0.192 AC: 56 AN: 292

European-Non Finnish (NFE) AF: 0.263 AC: 17885 AN: 67982

Other (OTH) AF: 0.273 AC: 577 AN: 2112

Alfa AF: 0.276 Hom.: 26289

Bravo AF: 0.279

Asia WGS AF: 0.535 AC: 1859 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.9
DANN	Benign	0.66
PhyloP100		1.5
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: rs2618476; hg19: chr8-11352541;