chr4-10490534-C-G

Variant names:

• chr4-10490534-C-G
• rs762033179
• NM_052964.4:c.1220G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052964.4(CLNK):​c.1220G>C​(p.Gly407Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000497 in 1,609,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G407E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CLNK NM_052964.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.65
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19320503).

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.1220G>C	p.Gly407Ala	missense	Exon 19 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.1220G>C	p.Gly407Ala	missense	Exon 19 of 19	ENSP00000226951.6	Q7Z7G1-1
	CLNK	ENST00000515667.5	TSL:3	c.434G>C	p.Gly145Ala	missense	Exon 5 of 5	ENSP00000427256.1	D6RJB9
	ENSG00000287154	ENST00000663264.1		n.96+33694C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000124 AC: 3 AN: 241382 AF XY: 0.0000153

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000274

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000480 AC: 7 AN: 1457512 Hom.: 0 Cov.: 30 AF XY: 0.00000276 AC XY: 2 AN XY: 724390

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25990

East Asian (EAS) AF: 0.00 AC: 0 AN: 39636

South Asian (SAS) AF: 0.00 AC: 0 AN: 85004

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109990

Other (OTH) AF: 0.0000166 AC: 1 AN: 60274

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000102105), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152098 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41402

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000434 Hom.: 0

ExAC AF: 0.0000248 AC: 3

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.0098
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.3	L
PhyloP100		4.6
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Benign	0.28	T
Sift4G	Benign	0.28	T
Polyphen		1.0	D
Vest4		0.30
MutPred		0.32		Loss of disorder (P = 0.0896)
MVP		0.54
MPC		0.031
ClinPred		0.46	T
GERP RS		4.1
Varity_R		0.048
gMVP		0.39
Mutation Taster		=81/19	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: rs762033179; hg19: chr4-10492158;