10-96230827-A-G

Variant names:

• chr10-96230827-A-G
• rs727852
• NM_013314.4:c.171T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013314.4(BLNK):​c.171T>C​(p.Pro57Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 1,609,256 control chromosomes in the GnomAD database, including 384,878 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (28143 hom., cov: 31)
  • Exomes 𝑓: 0.69 (356735 hom.)
• Consequence: BLNK NM_013314.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.102
• Publications: 23 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• autosomal agammaglobulinemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-96230827-A-G is Benign according to our data. Variant chr10-96230827-A-G is described in ClinVar as Benign. ClinVar VariationId is 402427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.102 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013314.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLNK	NM_013314.4	MANE Select	c.171T>C	p.Pro57Pro	synonymous	Exon 4 of 17	NP_037446.1	Q8WV28-1
	BLNK	NM_001114094.2		c.171T>C	p.Pro57Pro	synonymous	Exon 4 of 16	NP_001107566.1	Q8WV28-2
	BLNK	NM_001258440.2		c.171T>C	p.Pro57Pro	synonymous	Exon 4 of 16	NP_001245369.1	Q8WV28-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BLNK	ENST00000224337.10	TSL:1 MANE Select	c.171T>C	p.Pro57Pro	synonymous	Exon 4 of 17	ENSP00000224337.6	Q8WV28-1
	BLNK	ENST00000371176.7	TSL:1	c.171T>C	p.Pro57Pro	synonymous	Exon 4 of 16	ENSP00000360218.2	Q8WV28-2
	BLNK	ENST00000413476.6	TSL:1	c.171T>C	p.Pro57Pro	synonymous	Exon 4 of 16	ENSP00000397487.2	Q8WV28-3

Frequencies

GnomAD3 genomes AF: 0.568 AC: 86256 AN: 151908 Hom.: 28148 Cov.: 31

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.720

Gnomad AMR AF: 0.657

Gnomad ASJ AF: 0.675

Gnomad EAS AF: 0.475

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.728

Gnomad OTH AF: 0.580

GnomAD2 exomes AF: 0.640 AC: 155908 AN: 243678 AF XY: 0.640

Gnomad AFR exome AF: 0.225

Gnomad AMR exome AF: 0.716

Gnomad ASJ exome AF: 0.680

Gnomad EAS exome AF: 0.467

Gnomad FIN exome AF: 0.739

Gnomad NFE exome AF: 0.717

Gnomad OTH exome AF: 0.668

GnomAD4 exome AF: 0.692 AC: 1008599 AN: 1457230 Hom.: 356735 Cov.: 55 AF XY: 0.687 AC XY: 497802 AN XY: 724264

African (AFR) AF: 0.214 AC: 7171 AN: 33458

American (AMR) AF: 0.708 AC: 31188 AN: 44072

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 17571 AN: 26016

East Asian (EAS) AF: 0.497 AC: 19674 AN: 39620

South Asian (SAS) AF: 0.502 AC: 42758 AN: 85096

European-Finnish (FIN) AF: 0.737 AC: 39104 AN: 53076

Middle Eastern (MID) AF: 0.558 AC: 3211 AN: 5758

European-Non Finnish (NFE) AF: 0.728 AC: 808523 AN: 1109876

Other (OTH) AF: 0.654 AC: 39399 AN: 60258

GnomAD4 genome AF: 0.567 AC: 86263 AN: 152026 Hom.: 28143 Cov.: 31 AF XY: 0.568 AC XY: 42220 AN XY: 74310

African (AFR) AF: 0.236 AC: 9777 AN: 41490

American (AMR) AF: 0.657 AC: 10026 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.675 AC: 2341 AN: 3468

East Asian (EAS) AF: 0.475 AC: 2441 AN: 5144

South Asian (SAS) AF: 0.493 AC: 2368 AN: 4802

European-Finnish (FIN) AF: 0.735 AC: 7776 AN: 10580

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.728 AC: 49484 AN: 67956

Other (OTH) AF: 0.577 AC: 1219 AN: 2112

Alfa AF: 0.682 Hom.: 101224

Bravo AF: 0.551

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Agammaglobulinemia 4, autosomal recessive (2)
-	-	2	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.63
DANN	Benign	0.50
PhyloP100		-0.10
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: rs727852; hg19: chr10-97990583; COSMIC: COSV56409700; COSMIC: COSV56409700;