4-10501313-T-G

Variant names:

• chr4-10501313-T-G
• rs2903960
• NM_052964.4:c.1083A>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_052964.4(CLNK):​c.1083A>C​(p.Ile361Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,607,450 control chromosomes in the GnomAD database, including 801,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75081 hom., cov: 33)
  • Exomes 𝑓: 1.0 (726399 hom.)
• Consequence: CLNK NM_052964.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.610
• Publications: 14 publications found

Genes affected

CLNK (HGNC:17438): (cytokine dependent hematopoietic cell linker) MIST is a member of the SLP76 family of adaptors (see LCP2, MIM 601603; BLNK, MIM 604515). MIST plays a role in the regulation of immunoreceptor signaling, including PLC-gamma (PLCG1; MIM 172420)-mediated B cell antigen receptor (BCR) signaling and FC-epsilon R1 (see FCER1A, MIM 147140)-mediated mast cell degranulation (Cao et al., 1999 [PubMed 10562326]; Goitsuka et al., 2000, 2001 [PubMed 10744659] [PubMed 11463797]).[supplied by OMIM, Mar 2008]

ENSG00000287154 (HGNC:58732):

LOC105374482 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 4-10501313-T-G is Benign according to our data. Variant chr4-10501313-T-G is described in ClinVar as Benign. ClinVar VariationId is 402544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.61 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLNK	NM_052964.4	c.1083A>C	p.Ile361Ile	synonymous_variant	Exon 18 of 19	ENST00000226951.11	NP_443196.2
CLNK	XM_011513775.3	c.1128A>C	p.Ile376Ile	synonymous_variant	Exon 18 of 19		XP_011512077.1
CLNK	XM_017007684.2	c.1128A>C	p.Ile376Ile	synonymous_variant	Exon 18 of 19		XP_016863173.1
LOC105374482	XR_925387.4	n.261+4758T>G		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLNK	ENST00000226951.11	c.1083A>C	p.Ile361Ile	synonymous_variant	Exon 18 of 19	1	NM_052964.4	ENSP00000226951.6
CLNK	ENST00000515667.5	c.297A>C	p.Ile99Ile	synonymous_variant	Exon 4 of 5	3		ENSP00000427256.1
ENSG00000287154	ENST00000663264.1	n.97-28821T>G		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.993 AC: 151117 AN: 152214 Hom.: 75028 Cov.: 33

Gnomad AFR AF: 0.975

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.998

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.993

GnomAD2 exomes AF: 0.998 AC: 242344 AN: 242832 AF XY: 0.998

Gnomad AFR exome AF: 0.973

Gnomad AMR exome AF: 0.998

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1453948 AN: 1455118 Hom.: 726399 Cov.: 45 AF XY: 0.999 AC XY: 723294 AN XY: 723808

African (AFR) AF: 0.974 AC: 32129 AN: 32996

American (AMR) AF: 0.998 AC: 42831 AN: 42898

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 25980 AN: 25980

East Asian (EAS) AF: 1.00 AC: 39428 AN: 39428

South Asian (SAS) AF: 1.00 AC: 84877 AN: 84880

European-Finnish (FIN) AF: 1.00 AC: 53346 AN: 53346

Middle Eastern (MID) AF: 0.998 AC: 5732 AN: 5742

European-Non Finnish (NFE) AF: 1.00 AC: 1109615 AN: 1109724

Other (OTH) AF: 0.998 AC: 60010 AN: 60124

GnomAD4 genome AF: 0.993 AC: 151229 AN: 152332 Hom.: 75081 Cov.: 33 AF XY: 0.993 AC XY: 73935 AN XY: 74490

African (AFR) AF: 0.975 AC: 40524 AN: 41570

American (AMR) AF: 0.998 AC: 15273 AN: 15308

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3470 AN: 3470

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5170

South Asian (SAS) AF: 1.00 AC: 4831 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10624 AN: 10624

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68030 AN: 68036

Other (OTH) AF: 0.993 AC: 2102 AN: 2116

Alfa AF: 0.997 Hom.: 33359

Bravo AF: 0.992

Asia WGS AF: 0.997 AC: 3466 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

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	-0.50
CADD	Benign	7.3
DANN	Benign	0.81
PhyloP100		0.61
Mutation Taster		=91/9	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: rs2903960; hg19: chr4-10502937; COSMIC: COSV108089333;