rs61759824

Variant names:

• chr4-10584947-G-A
• rs61759824
• NM_052964.4:c.92C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052964.4(CLNK):​c.92C>T​(p.Pro31Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0523 in 1,613,330 control chromosomes in the GnomAD database, including 2,511 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.041 (187 hom., cov: 32)
  • Exomes 𝑓: 0.053 (2324 hom.)
• Consequence: CLNK NM_052964.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.92
• Publications: 6 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022577345).
• BP6: Variant 4-10584947-G-A is Benign according to our data. Variant chr4-10584947-G-A is described in ClinVar as Benign. ClinVar VariationId is 402545.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

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.92C>T	p.Pro31Leu	missense	Exon 4 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.92C>T	p.Pro31Leu	missense	Exon 4 of 19	ENSP00000226951.6	Q7Z7G1-1
	CLNK	ENST00000507719.1	TSL:1	c.-35C>T		5_prime_UTR	Exon 4 of 13	ENSP00000427208.1	Q7Z7G1-2

Frequencies

GnomAD3 genomes AF: 0.0407 AC: 6190 AN: 152116 Hom.: 186 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0384

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.0367

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0589

Gnomad OTH AF: 0.0530

GnomAD2 exomes AF: 0.0432 AC: 10731 AN: 248444 AF XY: 0.0454

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.0341

Gnomad ASJ exome AF: 0.0566

Gnomad EAS exome AF: 0.000279

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0570

Gnomad OTH exome AF: 0.0499

GnomAD4 exome AF: 0.0535 AC: 78149 AN: 1461096 Hom.: 2324 Cov.: 31 AF XY: 0.0538 AC XY: 39134 AN XY: 726774

African (AFR) AF: 0.0146 AC: 488 AN: 33468

American (AMR) AF: 0.0349 AC: 1562 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0577 AC: 1507 AN: 26128

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39694

South Asian (SAS) AF: 0.0394 AC: 3394 AN: 86114

European-Finnish (FIN) AF: 0.0386 AC: 2060 AN: 53386

Middle Eastern (MID) AF: 0.0619 AC: 357 AN: 5764

European-Non Finnish (NFE) AF: 0.0593 AC: 65890 AN: 1111488

Other (OTH) AF: 0.0477 AC: 2882 AN: 60360

GnomAD4 genome AF: 0.0407 AC: 6190 AN: 152234 Hom.: 187 Cov.: 32 AF XY: 0.0405 AC XY: 3012 AN XY: 74430

African (AFR) AF: 0.0150 AC: 621 AN: 41530

American (AMR) AF: 0.0383 AC: 586 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3472

East Asian (EAS) AF: 0.000772 AC: 4 AN: 5184

South Asian (SAS) AF: 0.0342 AC: 165 AN: 4818

European-Finnish (FIN) AF: 0.0367 AC: 389 AN: 10588

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0589 AC: 4006 AN: 68020

Other (OTH) AF: 0.0525 AC: 111 AN: 2116

Alfa AF: 0.0521 Hom.: 490

Bravo AF: 0.0402

TwinsUK AF: 0.0596 AC: 221

ALSPAC AF: 0.0651 AC: 251

ESP6500AA AF: 0.0118 AC: 48

ESP6500EA AF: 0.0617 AC: 515

ExAC AF: 0.0426 AC: 5155

Asia WGS AF: 0.0150 AC: 53 AN: 3478

EpiCase AF: 0.0638

EpiControl AF: 0.0623

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.084
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.58	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.9
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.12
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.99	D
Vest4		0.15
MPC		0.0065
ClinPred		0.027	T
GERP RS		3.9
Varity_R		0.13
gMVP		0.064
Mutation Taster		=94/6	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: rs61759824; hg19: chr4-10586571;