rs4841558

Variant names:

• chr8-11558088-C-T
• rs4841558
• NM_001715.3:c.1029+50C>T

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.1029+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 1,576,564 control chromosomes in the GnomAD database, including 275,910 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25763 hom., cov: 33)
  • Exomes 𝑓: 0.58 (250147 hom.)
• Consequence: BLK NM_001715.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.51
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-11558088-C-T is Benign according to our data. Variant chr8-11558088-C-T is described in ClinVar as Benign. ClinVar VariationId is 1253200.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.613 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.1029+50C>T		intron	N/A	NP_001706.2
	BLK	NM_001330465.2		c.816+50C>T		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.1029+50C>T		intron	N/A	ENSP00000259089.4
	ENSG00000269954	ENST00000602626.2	TSL:6	n.242-110G>A		intron	N/A
	BLK	ENST00000645242.1		n.1180+50C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86623 AN: 151952 Hom.: 25759 Cov.: 33

Gnomad AFR AF: 0.614

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.461

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.0586

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.618

Gnomad OTH AF: 0.554

GnomAD2 exomes AF: 0.520 AC: 129183 AN: 248324 AF XY: 0.523

Gnomad AFR exome AF: 0.624

Gnomad AMR exome AF: 0.375

Gnomad ASJ exome AF: 0.659

Gnomad EAS exome AF: 0.0602

Gnomad FIN exome AF: 0.567

Gnomad NFE exome AF: 0.619

Gnomad OTH exome AF: 0.565

GnomAD4 exome AF: 0.583 AC: 830270 AN: 1424494 Hom.: 250147 Cov.: 23 AF XY: 0.581 AC XY: 412992 AN XY: 710888

African (AFR) AF: 0.626 AC: 20479 AN: 32690

American (AMR) AF: 0.382 AC: 16923 AN: 44292

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 17015 AN: 25830

East Asian (EAS) AF: 0.0570 AC: 2246 AN: 39422

South Asian (SAS) AF: 0.458 AC: 39043 AN: 85310

European-Finnish (FIN) AF: 0.570 AC: 30239 AN: 53012

Middle Eastern (MID) AF: 0.615 AC: 3366 AN: 5476

European-Non Finnish (NFE) AF: 0.618 AC: 667499 AN: 1079412

Other (OTH) AF: 0.567 AC: 33460 AN: 59050

GnomAD4 genome AF: 0.570 AC: 86661 AN: 152070 Hom.: 25763 Cov.: 33 AF XY: 0.558 AC XY: 41510 AN XY: 74326

African (AFR) AF: 0.614 AC: 25445 AN: 41474

American (AMR) AF: 0.460 AC: 7037 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2265 AN: 3468

East Asian (EAS) AF: 0.0583 AC: 301 AN: 5162

South Asian (SAS) AF: 0.435 AC: 2097 AN: 4818

European-Finnish (FIN) AF: 0.552 AC: 5838 AN: 10574

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.618 AC: 41977 AN: 67964

Other (OTH) AF: 0.547 AC: 1156 AN: 2112

Alfa AF: 0.614 Hom.: 9419

Bravo AF: 0.560

Asia WGS AF: 0.275 AC: 962 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.31
DANN	Benign	0.64
PhyloP100		-2.5
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4841558; hg19: chr8-11415597; COSMIC: COSV52051446; COSMIC: COSV52051446;