chr2-105881413-C-A

Variant names:

• chr2-105881413-C-A
• rs767425900
• NM_003581.5:c.312C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003581.5(NCK2):​c.312C>A​(p.Ser104Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000685 in 1,460,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: NCK2 NM_003581.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.521
• Publications: 0 publications found

Genes affected

NCK2 (HGNC:7665): (NCK adaptor protein 2) This gene encodes a member of the NCK family of adaptor proteins. The protein contains three SH3 domains and one SH2 domain. The protein has no known catalytic function but has been shown to bind and recruit various proteins involved in the regulation of receptor protein tyrosine kinases. It is through these regulatory activities that this protein is believed to be involved in cytoskeletal reorganization. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ENSG00000234162 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09954667).
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003581.5. 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
	NCK2	NM_003581.5	MANE Select	c.312C>A	p.Ser104Arg	missense	Exon 4 of 5	NP_003572.2
	NCK2	NM_001004720.3		c.312C>A	p.Ser104Arg	missense	Exon 3 of 4	NP_001004720.1	A0A0S2Z4M6
	NCK2	NM_001004722.4		c.227-11569C>A		intron	N/A	NP_001004722.1	E7ERP6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCK2	ENST00000233154.9	TSL:5 MANE Select	c.312C>A	p.Ser104Arg	missense	Exon 4 of 5	ENSP00000233154.4	O43639
	NCK2	ENST00000393349.2	TSL:1	c.312C>A	p.Ser104Arg	missense	Exon 3 of 4	ENSP00000377018.2	O43639
	NCK2	ENST00000958280.1		c.330C>A	p.Ser110Arg	missense	Exon 5 of 6	ENSP00000628339.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000162 AC: 4 AN: 247670 AF XY: 0.0000297

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460330 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726540

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111904

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

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	0.55
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.45
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.52
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.090
Sift	Benign	0.059	T
Sift4G	Benign	0.49	T
Polyphen		0.0040	B
Vest4		0.33
MutPred		0.32		Loss of glycosylation at S104 (P = 0.0081)
MVP		0.30
MPC		1.3
ClinPred		0.16	T
GERP RS		1.4
Varity_R		0.28
gMVP		0.51
Mutation Taster		=73/27	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: rs767425900; hg19: chr2-106497869;