8-11564284-C-T

Variant names:

• chr8-11564284-C-T
• rs1042689
• ENST00000526097.1:n.1634C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000526097.1(BLK):​n.1634C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 779,138 control chromosomes in the GnomAD database, including 76,725 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15566 hom., cov: 35)
  • Exomes 𝑓: 0.42 (61159 hom.)
• Consequence: BLK ENST00000526097.1 non_coding_transcript_exon
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0230
• Publications: 11 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

ENSG00000269954 (HGNC:58190):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-11564284-C-T is Benign according to our data. Variant chr8-11564284-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 361500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLK	NM_001715.3	c.*176C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000259089.9	NP_001706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLK	ENST00000259089.9	c.*176C>T		3_prime_UTR_variant	Exon 13 of 13	1	NM_001715.3	ENSP00000259089.4

Frequencies

GnomAD3 genomes AF: 0.437 AC: 66462 AN: 152096 Hom.: 15539 Cov.: 35

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.522

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.923

Gnomad SAS AF: 0.507

Gnomad FIN AF: 0.430

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.426

GnomAD2 exomes AF: 0.483 AC: 61432 AN: 127312 AF XY: 0.476

Gnomad AFR exome AF: 0.482

Gnomad AMR exome AF: 0.597

Gnomad ASJ exome AF: 0.340

Gnomad EAS exome AF: 0.923

Gnomad FIN exome AF: 0.412

Gnomad NFE exome AF: 0.360

Gnomad OTH exome AF: 0.429

GnomAD4 exome AF: 0.416 AC: 261107 AN: 626924 Hom.: 61159 Cov.: 8 AF XY: 0.417 AC XY: 138457 AN XY: 331880

African (AFR) AF: 0.472 AC: 8014 AN: 16970

American (AMR) AF: 0.590 AC: 20266 AN: 34378

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 7098 AN: 20170

East Asian (EAS) AF: 0.919 AC: 29555 AN: 32152

South Asian (SAS) AF: 0.492 AC: 30931 AN: 62920

European-Finnish (FIN) AF: 0.407 AC: 13414 AN: 32934

Middle Eastern (MID) AF: 0.360 AC: 1511 AN: 4202

European-Non Finnish (NFE) AF: 0.350 AC: 136453 AN: 390308

Other (OTH) AF: 0.422 AC: 13865 AN: 32890

GnomAD4 genome AF: 0.437 AC: 66542 AN: 152214 Hom.: 15566 Cov.: 35 AF XY: 0.447 AC XY: 33268 AN XY: 74418

African (AFR) AF: 0.473 AC: 19652 AN: 41528

American (AMR) AF: 0.522 AC: 7989 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 1233 AN: 3472

East Asian (EAS) AF: 0.923 AC: 4780 AN: 5176

South Asian (SAS) AF: 0.505 AC: 2438 AN: 4826

European-Finnish (FIN) AF: 0.430 AC: 4558 AN: 10608

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24372 AN: 67996

Other (OTH) AF: 0.434 AC: 915 AN: 2110

Alfa AF: 0.393 Hom.: 7121

Bravo AF: 0.452

Asia WGS AF: 0.698 AC: 2424 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Systemic lupus erythematosus Benign:1

-

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

BLK gene is associated with Systemic lupus erythematosus, sjogren's syndrome and other systemic inflammatory conditions. However no sufficient evidence is found to ascertain the role of this particular variant rs1042689, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.2
DANN	Benign	0.80
PhyloP100		0.023
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: rs1042689; hg19: chr8-11421793;