rs148612299

Variant names:

• chr10-96223879-C-A
• rs148612299
• NM_013314.4:c.472G>T

Your query was ambiguous. Multiple possible variants found:

• chr10-96223879-C-A
• chr10-96223879-C-T

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.472G>T​(p.Ala158Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00514 in 1,613,884 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (48 hom.)
• Consequence: BLNK NM_013314.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.429
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002996534).
• BP6: Variant 10-96223879-C-A is Benign according to our data. Variant chr10-96223879-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 252680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00494 (752/152244) while in subpopulation AMR AF = 0.00628 (96/15296). AF 95% confidence interval is 0.00526. There are 6 homozygotes in GnomAd4. There are 386 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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.472G>T	p.Ala158Ser	missense	Exon 6 of 17	NP_037446.1	Q8WV28-1
	BLNK	NM_001114094.2		c.472G>T	p.Ala158Ser	missense	Exon 6 of 16	NP_001107566.1	Q8WV28-2
	BLNK	NM_001258440.2		c.472G>T	p.Ala158Ser	missense	Exon 6 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.472G>T	p.Ala158Ser	missense	Exon 6 of 17	ENSP00000224337.6	Q8WV28-1
	BLNK	ENST00000371176.7	TSL:1	c.472G>T	p.Ala158Ser	missense	Exon 6 of 16	ENSP00000360218.2	Q8WV28-2
	BLNK	ENST00000413476.6	TSL:1	c.472G>T	p.Ala158Ser	missense	Exon 6 of 16	ENSP00000397487.2	Q8WV28-3

Frequencies

GnomAD3 genomes AF: 0.00494 AC: 752 AN: 152126 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.00628

Gnomad ASJ AF: 0.0381

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00829

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.00494

Gnomad OTH AF: 0.00766

GnomAD2 exomes AF: 0.00605 AC: 1521 AN: 251470 AF XY: 0.00611

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00702

Gnomad ASJ exome AF: 0.0369

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00702

Gnomad NFE exome AF: 0.00527

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.00516 AC: 7540 AN: 1461640 Hom.: 48 Cov.: 32 AF XY: 0.00532 AC XY: 3865 AN XY: 727120

African (AFR) AF: 0.00143 AC: 48 AN: 33472

American (AMR) AF: 0.00771 AC: 345 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0353 AC: 923 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00333 AC: 287 AN: 86238

European-Finnish (FIN) AF: 0.00535 AC: 286 AN: 53414

Middle Eastern (MID) AF: 0.0167 AC: 93 AN: 5580

European-Non Finnish (NFE) AF: 0.00466 AC: 5179 AN: 1112006

Other (OTH) AF: 0.00628 AC: 379 AN: 60370

GnomAD4 genome AF: 0.00494 AC: 752 AN: 152244 Hom.: 6 Cov.: 32 AF XY: 0.00518 AC XY: 386 AN XY: 74446

African (AFR) AF: 0.00103 AC: 43 AN: 41550

American (AMR) AF: 0.00628 AC: 96 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0381 AC: 132 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4820

European-Finnish (FIN) AF: 0.00829 AC: 88 AN: 10610

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00494 AC: 336 AN: 68012

Other (OTH) AF: 0.00806 AC: 17 AN: 2110

Alfa AF: 0.00588 Hom.: 24

Bravo AF: 0.00526

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.00548 AC: 665

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00791

EpiControl AF: 0.00859

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Agammaglobulinemia 4, autosomal recessive (4)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	BLNK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.098
DANN	Benign	0.45
DEOGEN2	Benign	0.30	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0065	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.59	N
PhyloP100		-0.43
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.71	N
REVEL	Benign	0.032
Sift	Benign	0.55	T
Sift4G	Benign	0.56	T
Polyphen		0.0	B
Vest4		0.028
MVP		0.21
MPC		0.29
ClinPred		0.0026	T
GERP RS		-6.9
Varity_R		0.039
gMVP		0.13
Mutation Taster		=98/2	polymorphism

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: rs148612299; hg19: chr10-97983635; COSMIC: COSV56412312;