2-132728905-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_207363.3(NCKAP5):c.5491A>G(p.Thr1831Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,461,686 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1831I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000030 (1 hom.)
• Consequence: NCKAP5 NM_207363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.636

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044869035).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCKAP5	NM_207363.3	c.5491A>G	p.Thr1831Ala	missense_variant	18/20	ENST00000409261.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCKAP5	ENST00000409261.6	c.5491A>G	p.Thr1831Ala	missense_variant	18/20	5	NM_207363.3	P1
	ENST00000651100.1	n.457+42440T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000602 AC: 15 AN: 249042 Hom.: 0 AF XY: 0.0000814 AC XY: 11 AN XY: 135086

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000425

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461686 Hom.: 1 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 727126

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: 0.000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome Cov.: 32

Alfa AF: 0.000211 Hom.: 0

ExAC AF: 0.0000910 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

May 03, 2023

The c.5491A>G (p.T1831A) alteration is located in exon 18 (coding exon 16) of the NCKAP5 gene. This alteration results from a A to G substitution at nucleotide position 5491, causing the threonine (T) at amino acid position 1831 to be replaced by an alanine (A). 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	0.072
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	14
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0056	T;.;T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.045	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	N;N;N;N
REVEL	Benign	0.019
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.016	D;D;T;T
Polyphen		0.021	B;.;.;B
Vest4		0.24
MutPred		0.10		Loss of phosphorylation at T1831 (P = 0.0137);Loss of phosphorylation at T1831 (P = 0.0137);.;.;
MVP		0.17
MPC		0.041
ClinPred		0.11	T
GERP RS		0.92
Varity_R		0.060
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs768083355; hg19: chr2-133486478;