10-96216739-C-G

Variant names:

• chr10-96216739-C-G
• rs17111459
• NM_013314.4:c.526-5G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_013314.4(BLNK):​c.526-5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00759 in 1,612,622 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (68 hom.)
• Consequence: BLNK NM_013314.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002228
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.188
• Publications: 6 publications found

Genes affected

BLNK (HGNC:14211): (B cell linker) This gene encodes a cytoplasmic linker or adaptor protein that plays a critical role in B cell development. This protein bridges B cell receptor-associated kinase activation with downstream signaling pathways, thereby affecting various biological functions. The phosphorylation of five tyrosine residues is necessary for this protein to nucleate distinct signaling effectors following B cell receptor activation. Mutations in this gene cause hypoglobulinemia and absent B cells, a disease in which the pro- to pre-B-cell transition is developmentally blocked. Deficiency in this protein has also been shown in some cases of pre-B acute lymphoblastic leukemia. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, May 2012]

BLNK Gene-Disease associations (from GenCC):

• agammaglobulinemia 4, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-96216739-C-G is Benign according to our data. Variant chr10-96216739-C-G is described in ClinVar as Benign. ClinVar VariationId is 471481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.012 (1825/152176) while in subpopulation AFR AF = 0.024 (998/41526). AF 95% confidence interval is 0.0228. There are 22 homozygotes in GnomAd4. There are 868 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLNK	NM_013314.4	c.526-5G>C		splice_region_variant, intron_variant	Intron 6 of 16	ENST00000224337.10	NP_037446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLNK	ENST00000224337.10	c.526-5G>C		splice_region_variant, intron_variant	Intron 6 of 16	1	NM_013314.4	ENSP00000224337.6

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1820 AN: 152058 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0240

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00725

Gnomad FIN AF: 0.00180

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00823

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00699 AC: 1755 AN: 251020 AF XY: 0.00705

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.00544

Gnomad ASJ exome AF: 0.00656

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00222

Gnomad NFE exome AF: 0.00759

Gnomad OTH exome AF: 0.00883

GnomAD4 exome AF: 0.00713 AC: 10410 AN: 1460446 Hom.: 68 Cov.: 29 AF XY: 0.00722 AC XY: 5247 AN XY: 726652

African (AFR) AF: 0.0238 AC: 796 AN: 33446

American (AMR) AF: 0.00577 AC: 258 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00567 AC: 148 AN: 26114

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39688

South Asian (SAS) AF: 0.00536 AC: 462 AN: 86220

European-Finnish (FIN) AF: 0.00247 AC: 132 AN: 53384

Middle Eastern (MID) AF: 0.0179 AC: 103 AN: 5768

European-Non Finnish (NFE) AF: 0.00722 AC: 8017 AN: 1110796

Other (OTH) AF: 0.00816 AC: 492 AN: 60322

GnomAD4 genome AF: 0.0120 AC: 1825 AN: 152176 Hom.: 22 Cov.: 32 AF XY: 0.0117 AC XY: 868 AN XY: 74388

African (AFR) AF: 0.0240 AC: 998 AN: 41526

American (AMR) AF: 0.0101 AC: 154 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00547 AC: 19 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4824

European-Finnish (FIN) AF: 0.00180 AC: 19 AN: 10574

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.00823 AC: 560 AN: 68004

Other (OTH) AF: 0.0161 AC: 34 AN: 2110

Alfa AF: 0.00847 Hom.: 0

Bravo AF: 0.0121

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Agammaglobulinemia 4, autosomal recessive Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BLNK-related disorder Benign:1

Jul 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.34
DANN	Benign	0.51
PhyloP100		0.19
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0080
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: rs17111459; hg19: chr10-97976495;