rs2250788

Variant names:

• chr8-11494547-A-G
• rs2250788
• ENST00000525389.1:n.379A>G

Your query was ambiguous. Multiple possible variants found:

• chr8-11494547-A-G
• chr8-11494547-A-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.-46A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 152,266 control chromosomes in the GnomAD database, including 51,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (51503 hom., cov: 33)
  • Exomes 𝑓: 0.81 (15 hom.)
• Consequence: BLK NM_001715.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00
• Publications: 14 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=-0.87).
• BP6: Variant 8-11494547-A-G is Benign according to our data. Variant chr8-11494547-A-G is described in ClinVar as [Benign]. Clinvar id is 361471.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLK	NM_001715.3	c.-46A>G		5_prime_UTR_variant	Exon 1 of 13	ENST00000259089.9	NP_001706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLK	ENST00000525389.1	n.379A>G		non_coding_transcript_exon_variant	Exon 1 of 2	1
BLK	ENST00000259089.9	c.-46A>G		5_prime_UTR_variant	Exon 1 of 13	1	NM_001715.3	ENSP00000259089.4
BLK	ENST00000645242.1	n.274+7380A>G		intron_variant	Intron 1 of 11
BLK	ENST00000696154.2	n.274+7380A>G		intron_variant	Intron 1 of 11

Frequencies

GnomAD3 genomes AF: 0.821 AC: 124904 AN: 152108 Hom.: 51462 Cov.: 33

Gnomad AFR AF: 0.827

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.863

Gnomad ASJ AF: 0.830

Gnomad EAS AF: 0.736

Gnomad SAS AF: 0.796

Gnomad FIN AF: 0.698

Gnomad MID AF: 0.842

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.814

GnomAD4 exome AF: 0.810 AC: 34 AN: 42 Hom.: 15 Cov.: 0 AF XY: 0.861 AC XY: 31 AN XY: 36

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.824 AC: 28 AN: 34

Other (OTH) AF: 0.750 AC: 6 AN: 8

GnomAD4 genome AF: 0.821 AC: 125002 AN: 152224 Hom.: 51503 Cov.: 33 AF XY: 0.815 AC XY: 60632 AN XY: 74420

African (AFR) AF: 0.827 AC: 34331 AN: 41534

American (AMR) AF: 0.863 AC: 13209 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.830 AC: 2882 AN: 3472

East Asian (EAS) AF: 0.736 AC: 3816 AN: 5184

South Asian (SAS) AF: 0.796 AC: 3842 AN: 4826

European-Finnish (FIN) AF: 0.698 AC: 7386 AN: 10582

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.837 AC: 56952 AN: 68014

Other (OTH) AF: 0.817 AC: 1721 AN: 2106

Alfa AF: 0.842 Hom.: 24585

Bravo AF: 0.834

Asia WGS AF: 0.795 AC: 2765 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.46
PhyloP100		0.0
PromoterAI		0.076	Neutral
Mutation Taster		=300/0	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: rs2250788; hg19: chr8-11352056;