2-182934830-G-C

Variant names:

• chr2-182934830-G-C
• rs9288088
• NM_013436.5:c.2781C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_013436.5(NCKAP1):​c.2781C>G​(p.Val927Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.768 in 1,424,956 control chromosomes in the GnomAD database, including 430,417 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (37680 hom., cov: 32)
  • Exomes 𝑓: 0.78 (392737 hom.)
• Consequence: NCKAP1 NM_013436.5 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.341
• Publications: 23 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 2-182934830-G-C is Benign according to our data. Variant chr2-182934830-G-C is described in ClinVar as Benign. ClinVar VariationId is 1268390.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.341 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.938 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCKAP1	NM_013436.5	c.2781C>G	p.Val927Val	splice_region_variant, synonymous_variant	Exon 26 of 31	ENST00000361354.9	NP_038464.1
NCKAP1	NM_205842.3	c.2799C>G	p.Val933Val	splice_region_variant, synonymous_variant	Exon 27 of 32		NP_995314.1
NCKAP1	NM_001437267.1	c.2793C>G	p.Val931Val	splice_region_variant, synonymous_variant	Exon 27 of 32		NP_001424196.1
NCKAP1	NM_001437266.1	c.2775C>G	p.Val925Val	splice_region_variant, synonymous_variant	Exon 26 of 31		NP_001424195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCKAP1	ENST00000361354.9	c.2781C>G	p.Val927Val	splice_region_variant, synonymous_variant	Exon 26 of 31	1	NM_013436.5	ENSP00000355348.3

Frequencies

GnomAD3 genomes AF: 0.673 AC: 102225 AN: 151942 Hom.: 37667 Cov.: 32

Gnomad AFR AF: 0.349

Gnomad AMI AF: 0.857

Gnomad AMR AF: 0.756

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.960

Gnomad SAS AF: 0.872

Gnomad FIN AF: 0.870

Gnomad MID AF: 0.677

Gnomad NFE AF: 0.780

Gnomad OTH AF: 0.681

GnomAD2 exomes AF: 0.782 AC: 171399 AN: 219312 AF XY: 0.789

Gnomad AFR exome AF: 0.330

Gnomad AMR exome AF: 0.809

Gnomad ASJ exome AF: 0.701

Gnomad EAS exome AF: 0.955

Gnomad FIN exome AF: 0.865

Gnomad NFE exome AF: 0.775

Gnomad OTH exome AF: 0.782

GnomAD4 exome AF: 0.780 AC: 992663 AN: 1272896 Hom.: 392737 Cov.: 20 AF XY: 0.783 AC XY: 500696 AN XY: 639436

African (AFR) AF: 0.313 AC: 9460 AN: 30176

American (AMR) AF: 0.802 AC: 32604 AN: 40632

Ashkenazi Jewish (ASJ) AF: 0.701 AC: 17118 AN: 24418

East Asian (EAS) AF: 0.957 AC: 35919 AN: 37548

South Asian (SAS) AF: 0.862 AC: 66605 AN: 77234

European-Finnish (FIN) AF: 0.865 AC: 45062 AN: 52100

Middle Eastern (MID) AF: 0.702 AC: 3819 AN: 5438

European-Non Finnish (NFE) AF: 0.779 AC: 740781 AN: 951522

Other (OTH) AF: 0.767 AC: 41295 AN: 53828

GnomAD4 genome AF: 0.673 AC: 102272 AN: 152060 Hom.: 37680 Cov.: 32 AF XY: 0.681 AC XY: 50635 AN XY: 74362

African (AFR) AF: 0.349 AC: 14468 AN: 41428

American (AMR) AF: 0.756 AC: 11541 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2435 AN: 3470

East Asian (EAS) AF: 0.960 AC: 4973 AN: 5180

South Asian (SAS) AF: 0.873 AC: 4211 AN: 4826

European-Finnish (FIN) AF: 0.870 AC: 9212 AN: 10594

Middle Eastern (MID) AF: 0.667 AC: 196 AN: 294

European-Non Finnish (NFE) AF: 0.780 AC: 53017 AN: 67986

Other (OTH) AF: 0.682 AC: 1439 AN: 2110

Alfa AF: 0.741 Hom.: 13871

Bravo AF: 0.648

Asia WGS AF: 0.852 AC: 2935 AN: 3452

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 31, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NCKAP1-related disorder Benign:1

Oct 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	2.1
DANN	Benign	0.63
PhyloP100		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs9288088; hg19: chr2-183799558;