chr8-11548033-C-G

Position:

• chr8-11548033-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000259089.9(BLK):​c.177C>G​(p.Asp59Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,613,942 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D59G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0083 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00088 (14 hom.)
• Consequence: BLK ENST00000259089.9 missense, splice_region
• Scores: Splicing: ADA: 0.00005470
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.733

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030113757).
• BP6: Variant 8-11548033-C-G is Benign according to our data. Variant chr8-11548033-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 361475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-11548033-C-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00833 (1268/152294) while in subpopulation AFR AF= 0.028 (1162/41558). AF 95% confidence interval is 0.0266. There are 15 homozygotes in gnomad4. There are 610 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1268 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLK	NM_001715.3	c.177C>G	p.Asp59Glu	missense_variant, splice_region_variant	4/13	ENST00000259089.9	NP_001706.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLK	ENST00000259089.9	c.177C>G	p.Asp59Glu	missense_variant, splice_region_variant	4/13	1	NM_001715.3	ENSP00000259089	P1
BLK	ENST00000533828.1	n.375C>G		splice_region_variant, non_coding_transcript_exon_variant	2/3	4
BLK	ENST00000645242.1	n.328C>G		splice_region_variant, non_coding_transcript_exon_variant	3/12
BLK	ENST00000696154.2	n.328C>G		splice_region_variant, non_coding_transcript_exon_variant	3/12

Frequencies

GnomAD3 genomes AF: 0.00827 AC: 1259 AN: 152176 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0278

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00212 AC: 533 AN: 251456 Hom.: 6 AF XY: 0.00160 AC XY: 218 AN XY: 135912

Gnomad AFR exome AF: 0.0273

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000878 AC: 1284 AN: 1461648 Hom.: 14 Cov.: 31 AF XY: 0.000820 AC XY: 596 AN XY: 727148

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00192

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000980

Gnomad4 OTH exome AF: 0.00210

GnomAD4 genome AF: 0.00833 AC: 1268 AN: 152294 Hom.: 15 Cov.: 32 AF XY: 0.00819 AC XY: 610 AN XY: 74466

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00503

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00123 Hom.: 2

Bravo AF: 0.00935

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00257 AC: 312

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 17, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Monogenic diabetes Benign:1

Benign, criteria provided, single submitter

research

Personalized Diabetes Medicine Program, University of Maryland School of Medicine

Jan 13, 2017

ACMG Criteria:BP4 (9 predictors), BS1 (3.9% in African in 1000g and 2.7% in ExAC), BS2 (seen in 75 controls and 66 cases in type2diabetesgenetics.org) -

Systemic lupus erythematosus Benign:1

Benign, criteria provided, single submitter

research

Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic

-

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 rs146083915, yet. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.39
DANN	Benign	0.26
DEOGEN2	Benign	0.049	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.34	N
REVEL	Benign	0.056
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.21
MutPred		0.29		Gain of ubiquitination at K60 (P = 0.068);
MVP		0.71
MPC		0.021
ClinPred		0.0014	T
GERP RS		0.27
Varity_R		0.038
gMVP		0.10

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000055
dbscSNV1_RF	Benign	0.096
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.22		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs146083915; hg19: chr8-11405542;