NM_013314.4:c.88G>C

Variant names:

• chr10-96247009-C-G
• rs143109144
• NM_013314.4:c.88G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_013314.4(BLNK):​c.88G>C​(p.Gly30Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000949 in 1,607,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (0 hom.)
• Consequence: BLNK NM_013314.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.15
• Publications: 3 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.045404345).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000703 (107/152238) while in subpopulation NFE AF = 0.00121 (82/68012). AF 95% confidence interval is 0.000995. There are 0 homozygotes in GnomAd4. There are 50 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.88G>C	p.Gly30Arg	missense	Exon 2 of 17	NP_037446.1	Q8WV28-1
	BLNK	NM_001114094.2		c.88G>C	p.Gly30Arg	missense	Exon 2 of 16	NP_001107566.1	Q8WV28-2
	BLNK	NM_001258440.2		c.88G>C	p.Gly30Arg	missense	Exon 2 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.88G>C	p.Gly30Arg	missense	Exon 2 of 17	ENSP00000224337.6	Q8WV28-1
	BLNK	ENST00000371176.7	TSL:1	c.88G>C	p.Gly30Arg	missense	Exon 2 of 16	ENSP00000360218.2	Q8WV28-2
	BLNK	ENST00000413476.6	TSL:1	c.88G>C	p.Gly30Arg	missense	Exon 2 of 16	ENSP00000397487.2	Q8WV28-3

Frequencies

GnomAD3 genomes AF: 0.000703 AC: 107 AN: 152120 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000718 AC: 179 AN: 249474 AF XY: 0.000772

Gnomad AFR exome AF: 0.000186

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000649

Gnomad NFE exome AF: 0.00125

Gnomad OTH exome AF: 0.000822

GnomAD4 exome AF: 0.000974 AC: 1418 AN: 1455350 Hom.: 0 Cov.: 29 AF XY: 0.000935 AC XY: 677 AN XY: 723830

African (AFR) AF: 0.0000902 AC: 3 AN: 33262

American (AMR) AF: 0.0000225 AC: 1 AN: 44514

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 32 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39556

South Asian (SAS) AF: 0.00 AC: 0 AN: 84888

European-Finnish (FIN) AF: 0.000659 AC: 35 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00118 AC: 1311 AN: 1108112

Other (OTH) AF: 0.000598 AC: 36 AN: 60152

GnomAD4 genome AF: 0.000703 AC: 107 AN: 152238 Hom.: 0 Cov.: 33 AF XY: 0.000672 AC XY: 50 AN XY: 74446

African (AFR) AF: 0.000289 AC: 12 AN: 41522

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000660 AC: 7 AN: 10600

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

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.000627

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000750 AC: 91

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.21
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.36
MVP		0.71
MPC		1.2
ClinPred		0.13	T
GERP RS		5.7
Varity_R		0.27
gMVP		0.18
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs143109144; hg19: chr10-98006765; COSMIC: COSV106081319;