8-11543340-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001715.3(BLK):c.116C>T(p.Pro39Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00273 in 1,613,148 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (8 hom.)
• Consequence: BLK NM_001715.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.47

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021823794).
• BP6: Variant 8-11543340-C-T is Benign according to our data. Variant chr8-11543340-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 258175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11543340-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 300 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLK	NM_001715.3	c.116C>T	p.Pro39Leu	missense_variant	2/13	ENST00000259089.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLK	ENST00000259089.9	c.116C>T	p.Pro39Leu	missense_variant	2/13	1	NM_001715.3	P1
BLK	ENST00000645242.1	n.275-2712C>T		intron_variant, non_coding_transcript_variant
BLK	ENST00000696154.2	n.275-2712C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00197 AC: 300 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00320

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00222 AC: 554 AN: 249222 Hom.: 0 AF XY: 0.00239 AC XY: 323 AN XY: 134968

Gnomad AFR exome AF: 0.000687

Gnomad AMR exome AF: 0.00301

Gnomad ASJ exome AF: 0.000795

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.000832

Gnomad NFE exome AF: 0.00339

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00281 AC: 4103 AN: 1460846 Hom.: 8 Cov.: 35 AF XY: 0.00277 AC XY: 2016 AN XY: 726812

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00333

Gnomad4 ASJ exome AF: 0.000574

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.000638

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.00328

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00197 AC: 300 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74474

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00320

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00165 Hom.: 0

Bravo AF: 0.00208

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00227 AC: 276

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00256

EpiControl AF: 0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	BLK: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2019	This variant is associated with the following publications: (PMID: 32041611) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, no assertion criteria provided

research

Carola Vinuesa Lab, John Curtin School of Medical Research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.29
Sift	Benign	0.032	D
Sift4G	Uncertain	0.023	D
Polyphen		0.55	P
Vest4		0.62
MVP		0.88
MPC		0.074
ClinPred		0.030	T
GERP RS		5.5
Varity_R		0.092
gMVP		0.36

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

Publications

LitVar

Other links and lift over

dbSNP: rs142352008; hg19: chr8-11400849; COSMIC: COSV52049911; COSMIC: COSV52049911;