NM_013436.5:c.3180G>C

Variant names:

• chr2-182928117-C-G
• rs761671233
• NM_013436.5:c.3180G>C

Variant summary

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

The NM_013436.5(NCKAP1):​c.3180G>C​(p.Ala1060Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A1060A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: NCKAP1 NM_013436.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9948
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.135
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).

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.3180G>C	p.Ala1060Ala	splice_region synonymous	Exon 29 of 31	NP_038464.1	Q9Y2A7-1
	NCKAP1	NM_205842.3		c.3198G>C	p.Ala1066Ala	splice_region synonymous	Exon 30 of 32	NP_995314.1	Q9Y2A7-2
	NCKAP1	NM_001437267.1		c.3192G>C	p.Ala1064Ala	splice_region synonymous	Exon 30 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.3180G>C	p.Ala1060Ala	splice_region synonymous	Exon 29 of 31	ENSP00000355348.3	Q9Y2A7-1
	NCKAP1	ENST00000360982.2	TSL:1	c.3198G>C	p.Ala1066Ala	splice_region synonymous	Exon 30 of 32	ENSP00000354251.2	Q9Y2A7-2
	NCKAP1	ENST00000888539.1		c.3195G>C	p.Ala1065Ala	splice_region synonymous	Exon 29 of 31	ENSP00000558598.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433108 Hom.: 0 Cov.: 29 AF XY: 0.00000140 AC XY: 1 AN XY: 713746

African (AFR) AF: 0.00 AC: 0 AN: 32552

American (AMR) AF: 0.00 AC: 0 AN: 43096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25720

East Asian (EAS) AF: 0.00 AC: 0 AN: 39458

South Asian (SAS) AF: 0.00 AC: 0 AN: 83866

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5710

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090016

Other (OTH) AF: 0.00 AC: 0 AN: 59412

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.75
PhyloP100		-0.14
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.71
SpliceAI score (max)		0.040		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: rs761671233; hg19: chr2-183792845;