2-182928117-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCKAP1	NM_013436.5	c.3180G>C	p.Ala1060Ala	splice_region_variant, synonymous_variant	Exon 29 of 31	ENST00000361354.9	NP_038464.1
NCKAP1	NM_205842.3	c.3198G>C	p.Ala1066Ala	splice_region_variant, synonymous_variant	Exon 30 of 32		NP_995314.1
NCKAP1	XM_006712200.4	c.3192G>C	p.Ala1064Ala	splice_region_variant, synonymous_variant	Exon 30 of 32		XP_006712263.1
NCKAP1	XM_006712201.4	c.3174G>C	p.Ala1058Ala	splice_region_variant, synonymous_variant	Exon 29 of 31		XP_006712264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCKAP1	ENST00000361354.9	c.3180G>C	p.Ala1060Ala	splice_region_variant, synonymous_variant	Exon 29 of 31	1	NM_013436.5	ENSP00000355348.3

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.17e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	16
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs761671233; hg19: chr2-183792845;