chr4-10513558-C-A

Position:

• chr4-10513558-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052964.4(CLNK):​c.812G>T​(p.Cys271Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: CLNK NM_052964.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15781438).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CLNK	NM_052964.4	c.812G>T	p.Cys271Phe	missense_variant	16/19	ENST00000226951.11	NP_443196.2
LOC105374482	XR_925387.4	n.262-16572C>A		intron_variant, non_coding_transcript_variant
CLNK	XM_011513775.3	c.857G>T	p.Cys286Phe	missense_variant	16/19		XP_011512077.1
CLNK	XM_017007684.2	c.857G>T	p.Cys286Phe	missense_variant	16/19		XP_016863173.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CLNK	ENST00000226951.11	c.812G>T	p.Cys271Phe	missense_variant	16/19	1	NM_052964.4	ENSP00000226951	P1
	ENST00000663264.1	n.97-16576C>A		intron_variant, non_coding_transcript_variant
CLNK	ENST00000515667.5	c.26G>T	p.Cys9Phe	missense_variant	2/5	3		ENSP00000427256

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 08, 2023

The c.812G>T (p.C271F) alteration is located in exon 16 (coding exon 15) of the CLNK gene. This alteration results from a G to T substitution at nucleotide position 812, causing the cysteine (C) at amino acid position 271 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.42	T;.;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.0	M;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-4.0	D;D;.
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.27
MutPred		0.13		Loss of glycosylation at S276 (P = 0.08);.;Loss of glycosylation at S276 (P = 0.08);
MVP		0.25
MPC		0.028
ClinPred		0.95	D
GERP RS		3.4
Varity_R		0.59
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-10515182;