10-96227509-C-T

Variant names:

• chr10-96227509-C-T
• rs144903484
• NM_013314.4:c.262G>A

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.262G>A​(p.Ala88Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,614,202 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A88S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0068 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00068 (10 hom.)
• Consequence: BLNK NM_013314.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.38
• Publications: 2 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=0.0062735677).
• BP6: Variant 10-96227509-C-T is Benign according to our data. Variant chr10-96227509-C-T is described in ClinVar as Benign. ClinVar VariationId is 487218.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 = 0.0068 (1036/152366) while in subpopulation AFR AF = 0.0222 (925/41590). AF 95% confidence interval is 0.0211. There are 11 homozygotes in GnomAd4. There are 501 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.262G>A	p.Ala88Thr	missense	Exon 5 of 17	NP_037446.1	Q8WV28-1
	BLNK	NM_001114094.2		c.262G>A	p.Ala88Thr	missense	Exon 5 of 16	NP_001107566.1	Q8WV28-2
	BLNK	NM_001258440.2		c.262G>A	p.Ala88Thr	missense	Exon 5 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.262G>A	p.Ala88Thr	missense	Exon 5 of 17	ENSP00000224337.6	Q8WV28-1
	BLNK	ENST00000371176.7	TSL:1	c.262G>A	p.Ala88Thr	missense	Exon 5 of 16	ENSP00000360218.2	Q8WV28-2
	BLNK	ENST00000413476.6	TSL:1	c.262G>A	p.Ala88Thr	missense	Exon 5 of 16	ENSP00000397487.2	Q8WV28-3

Frequencies

GnomAD3 genomes AF: 0.00680 AC: 1036 AN: 152248 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00764

GnomAD2 exomes AF: 0.00175 AC: 439 AN: 251412 AF XY: 0.00129

Gnomad AFR exome AF: 0.0223

Gnomad AMR exome AF: 0.00173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000681 AC: 996 AN: 1461836 Hom.: 10 Cov.: 37 AF XY: 0.000580 AC XY: 422 AN XY: 727224

African (AFR) AF: 0.0221 AC: 739 AN: 33480

American (AMR) AF: 0.00228 AC: 102 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000927 AC: 8 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000504 AC: 56 AN: 1112008

Other (OTH) AF: 0.00132 AC: 80 AN: 60396

GnomAD4 genome AF: 0.00680 AC: 1036 AN: 152366 Hom.: 11 Cov.: 33 AF XY: 0.00672 AC XY: 501 AN XY: 74512

African (AFR) AF: 0.0222 AC: 925 AN: 41590

American (AMR) AF: 0.00536 AC: 82 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68038

Other (OTH) AF: 0.00756 AC: 16 AN: 2116

Alfa AF: 0.00238 Hom.: 5

Bravo AF: 0.00805

ESP6500AA AF: 0.0266 AC: 117

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00215 AC: 261

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Agammaglobulinemia 4, autosomal recessive (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.10	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.4
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.074
Sift	Uncertain	0.022	D
Sift4G	Benign	0.26	T
Polyphen		0.64	P
Vest4		0.33
MVP		0.50
MPC		0.54
ClinPred		0.020	T
GERP RS		5.8
Varity_R		0.065
gMVP		0.094
Mutation Taster		=94/6	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: rs144903484; hg19: chr10-97987265;