2-182935297-C-T

Variant names:

• chr2-182935297-C-T
• NM_013436.5:c.2774G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_013436.5(NCKAP1):​c.2774G>A​(p.Arg925Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCKAP1 NM_013436.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

Genes affected

NCKAP1 (HGNC:7666): (NCK associated protein 1) Contributes to small GTPase binding activity. Involved in Rac protein signal transduction; positive regulation of Arp2/3 complex-mediated actin nucleation; and positive regulation of lamellipodium assembly. Located in extracellular exosome and focal adhesion. Part of SCAR complex. [provided by Alliance of Genome Resources, Apr 2022]

NCKAP1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36664867).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013436.5. 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
	NCKAP1	NM_013436.5	MANE Select	c.2774G>A	p.Arg925Lys	missense	Exon 25 of 31	NP_038464.1	Q9Y2A7-1
	NCKAP1	NM_205842.3		c.2792G>A	p.Arg931Lys	missense	Exon 26 of 32	NP_995314.1	Q9Y2A7-2
	NCKAP1	NM_001437267.1		c.2786G>A	p.Arg929Lys	missense	Exon 26 of 32	NP_001424196.1	A0A994J6K9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCKAP1	ENST00000361354.9	TSL:1 MANE Select	c.2774G>A	p.Arg925Lys	missense	Exon 25 of 31	ENSP00000355348.3	Q9Y2A7-1
	NCKAP1	ENST00000360982.2	TSL:1	c.2792G>A	p.Arg931Lys	missense	Exon 26 of 32	ENSP00000354251.2	Q9Y2A7-2
	NCKAP1	ENST00000888539.1		c.2789G>A	p.Arg930Lys	missense	Exon 25 of 31	ENSP00000558598.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.020
Eigen_PC	Benign	0.19
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.30	N
PhyloP100		7.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.15
Sift	Benign	0.39	T
Sift4G	Benign	0.93	T
Polyphen		0.30	B
Vest4		0.52
MutPred		0.60		Gain of ubiquitination at R925 (P = 0.0539)
MVP		0.39
MPC		1.7
ClinPred		0.73	D
GERP RS		5.3
Varity_R		0.37
gMVP		0.66
Mutation Taster		=37/63	disease causing

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

hg19: chr2-183800025;