chr4-10501311-C-T

Variant names:

• chr4-10501311-C-T
• rs199925446
• NM_052964.4:c.1085G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_052964.4(CLNK):​c.1085G>A​(p.Arg362His) variant causes a missense change. The variant allele was found at a frequency of 0.000567 in 1,607,104 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R362C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: CLNK NM_052964.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.89
• Publications: 5 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: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.795

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052964.4. 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
	CLNK	NM_052964.4	MANE Select	c.1085G>A	p.Arg362His	missense	Exon 18 of 19	NP_443196.2	Q7Z7G1-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLNK	ENST00000226951.11	TSL:1 MANE Select	c.1085G>A	p.Arg362His	missense	Exon 18 of 19	ENSP00000226951.6	Q7Z7G1-1
	CLNK	ENST00000515667.5	TSL:3	c.299G>A	p.Arg100His	missense	Exon 4 of 5	ENSP00000427256.1	D6RJB9
	ENSG00000287154	ENST00000663264.1		n.97-28823C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 55 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000334 AC: 81 AN: 242328 AF XY: 0.000334

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.000126

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000466

Gnomad NFE exome AF: 0.000566

Gnomad OTH exome AF: 0.000344

GnomAD4 exome AF: 0.000588 AC: 856 AN: 1454818 Hom.: 1 Cov.: 29 AF XY: 0.000551 AC XY: 399 AN XY: 723580

African (AFR) AF: 0.000243 AC: 8 AN: 32982

American (AMR) AF: 0.0000934 AC: 4 AN: 42838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39416

South Asian (SAS) AF: 0.00 AC: 0 AN: 84806

European-Finnish (FIN) AF: 0.000600 AC: 32 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.000710 AC: 788 AN: 1109582

Other (OTH) AF: 0.000399 AC: 24 AN: 60122

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000322 AC XY: 24 AN XY: 74458

African (AFR) AF: 0.0000722 AC: 3 AN: 41560

American (AMR) AF: 0.000196 AC: 3 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000490 Hom.: 0

Bravo AF: 0.000412

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000485 AC: 4

ExAC AF: 0.000356 AC: 43

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.9
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0070	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MVP		0.58
MPC		0.032
ClinPred		0.73	D
GERP RS		5.4
Varity_R		0.48
gMVP		0.42
Mutation Taster		=62/38	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: rs199925446; hg19: chr4-10502935; COSMIC: COSV99904512;