2-132781059-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_207363.3(NCKAP5):c.5042A>T(p.Asp1681Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NCKAP5 NM_207363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.24

Genes affected

NCKAP5 (HGNC:29847): (NCK associated protein 5) Predicted to be involved in microtubule bundle formation and microtubule depolymerization. Predicted to be active in microtubule plus-end. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

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 (MetaRNN=0.11869356).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCKAP5	NM_207363.3	c.5042A>T	p.Asp1681Val	missense_variant	15/20	ENST00000409261.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCKAP5	ENST00000409261.6	c.5042A>T	p.Asp1681Val	missense_variant	15/20	5	NM_207363.3	P1
	ENST00000651100.1	n.458-33542T>A		intron_variant, non_coding_transcript_variant
NCKAP5	ENST00000409213.5	c.1093-7165A>T		intron_variant		5
NCKAP5	ENST00000473859.1	n.255A>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247712 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134326

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000828 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.5042A>T (p.D1681V) alteration is located in exon 15 (coding exon 13) of the NCKAP5 gene. This alteration results from a A to T substitution at nucleotide position 5042, causing the aspartic acid (D) at amino acid position 1681 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	20
Dann	Benign	0.60
DEOGEN2	Benign	0.0084	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.70
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.011	D;D
Sift4G	Benign	0.11	T;T
Polyphen		0.43	B;.
Vest4		0.34
MutPred		0.25		Loss of solvent accessibility (P = 0.0169);Loss of solvent accessibility (P = 0.0169);
MVP		0.11
MPC		0.082
ClinPred		0.15	T
GERP RS		3.0
Varity_R		0.13
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs758429982; hg19: chr2-133538632;