4-10513474-G-A

Variant names:

• chr4-10513474-G-A
• rs762619599
• NM_052964.4:c.896C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052964.4(CLNK):​c.896C>T​(p.Ser299Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CLNK NM_052964.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0560

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:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.055841923).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLNK	NM_052964.4	c.896C>T	p.Ser299Phe	missense_variant	Exon 16 of 19	ENST00000226951.11	NP_443196.2
CLNK	XM_011513775.3	c.941C>T	p.Ser314Phe	missense_variant	Exon 16 of 19		XP_011512077.1
CLNK	XM_017007684.2	c.941C>T	p.Ser314Phe	missense_variant	Exon 16 of 19		XP_016863173.1
LOC105374482	XR_925387.4	n.262-16656G>A		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLNK	ENST00000226951.11	c.896C>T	p.Ser299Phe	missense_variant	Exon 16 of 19	1	NM_052964.4	ENSP00000226951.6
CLNK	ENST00000515667.5	c.110C>T	p.Ser37Phe	missense_variant	Exon 2 of 5	3		ENSP00000427256.1
ENSG00000287154	ENST00000663264.1	n.97-16660G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD3 exomes AF: 0.0000245 AC: 6 AN: 245252 Hom.: 0 AF XY: 0.0000151 AC XY: 2 AN XY: 132836

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000337

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459180 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

Bravo AF: 0.00000378

ExAC AF: 0.0000248 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	3.7
DANN	Benign	0.80
DEOGEN2	Benign	0.39	T;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.056	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.5	N;D;.
REVEL	Benign	0.078
Sift	Benign	0.14	T;T;.
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.11
MutPred		0.39		Loss of phosphorylation at S299 (P = 0.0158);.;Loss of phosphorylation at S299 (P = 0.0158);
MVP		0.055
MPC		0.0064
ClinPred		0.027	T
GERP RS		2.4
Varity_R		0.061
gMVP		0.21

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

Publications

LitVar

Other links and lift over

dbSNP: rs762619599; hg19: chr4-10515098;