chr2-182928120-CAGAAATTCTTTA-C

Position:

• chr2-182928120-CAGAAATTCTTTA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM4 PP3 PP5_Moderate

The NM_013436.5(NCKAP1):​c.3165_3176delTAAAGAATTTCT​(p.Lys1056_Leu1059del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCKAP1 NM_013436.5 disruptive_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.22

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_013436.5.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 2-182928120-CAGAAATTCTTTA-C is Pathogenic according to our data. Variant chr2-182928120-CAGAAATTCTTTA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2530332.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCKAP1	NM_013436.5	c.3165_3176delTAAAGAATTTCT	p.Lys1056_Leu1059del	disruptive_inframe_deletion	29/31	ENST00000361354.9	NP_038464.1
NCKAP1	NM_205842.3	c.3183_3194delTAAAGAATTTCT	p.Lys1062_Leu1065del	disruptive_inframe_deletion	30/32		NP_995314.1
NCKAP1	XM_006712200.4	c.3177_3188delTAAAGAATTTCT	p.Lys1060_Leu1063del	disruptive_inframe_deletion	30/32		XP_006712263.1
NCKAP1	XM_006712201.4	c.3159_3170delTAAAGAATTTCT	p.Lys1054_Leu1057del	disruptive_inframe_deletion	29/31		XP_006712264.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCKAP1	ENST00000361354.9	c.3165_3176delTAAAGAATTTCT	p.Lys1056_Leu1059del	disruptive_inframe_deletion	29/31	1	NM_013436.5	ENSP00000355348.3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2023

The c.3183_3194del12 (p.K1062_L1065del) alteration, located in coding exon 30 of the NCKAP1 gene, results from an in-frame deletion of 12 nucleotides at positions c.3183 to c.3194. This results in the deletion of 4 amino acids from codons 1062 to 1065. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid region is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis (Choi, 2012). Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr2-183792848;