2-182925809-C-A

Position:

• chr2-182925809-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_013436.5(NCKAP1):​c.3280G>T​(p.Glu1094*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NCKAP1 NM_013436.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.82

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0316 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-182925809-C-A is Pathogenic according to our data. Variant chr2-182925809-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3064095.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-182925809-C-A is described in Lovd as [Likely_pathogenic]. Variant chr2-182925809-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCKAP1	NM_013436.5	c.3280G>T	p.Glu1094*	stop_gained	31/31	ENST00000361354.9	NP_038464.1
NCKAP1	NM_205842.3	c.3298G>T	p.Glu1100*	stop_gained	32/32		NP_995314.1
NCKAP1	XM_006712200.4	c.3292G>T	p.Glu1098*	stop_gained	32/32		XP_006712263.1
NCKAP1	XM_006712201.4	c.3274G>T	p.Glu1092*	stop_gained	31/31		XP_006712264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCKAP1	ENST00000361354.9	c.3280G>T	p.Glu1094*	stop_gained	31/31	1	NM_013436.5	ENSP00000355348.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1373186 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 683410

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency 72 with autoinflammation Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 17, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.36
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-183790537;