2-132781994-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.4817A>G(p.His1606Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NCKAP5 NM_207363.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.742

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=0.046001196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCKAP5	NM_207363.3	c.4817A>G	p.His1606Arg	missense_variant	14/20	ENST00000409261.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCKAP5	ENST00000409261.6	c.4817A>G	p.His1606Arg	missense_variant	14/20	5	NM_207363.3	P1
	ENST00000651100.1	n.458-32607T>C		intron_variant, non_coding_transcript_variant
NCKAP5	ENST00000409213.5	c.1092+8029A>G		intron_variant		5
NCKAP5	ENST00000473859.1	n.30A>G		non_coding_transcript_exon_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461656 Hom.: 0 Cov.: 72 AF XY: 0.00000138 AC XY: 1 AN XY: 727102

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Dec 15, 2022

The c.4817A>G (p.H1606R) alteration is located in exon 14 (coding exon 12) of the NCKAP5 gene. This alteration results from a A to G substitution at nucleotide position 4817, causing the histidine (H) at amino acid position 1606 to be replaced by an arginine (R). 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	-0.34	T
BayesDel_noAF	Benign	-0.72
Cadd	Benign	10
Dann	Benign	0.56
DEOGEN2	Benign	0.0037	T;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.046	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.55	N;.
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.80	N;N
REVEL	Benign	0.0090
Sift	Benign	0.34	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.037	B;.
Vest4		0.091
MutPred		0.26		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.068
MPC		0.051
ClinPred		0.11	T
GERP RS		1.0
Varity_R		0.057
gMVP		0.065

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-133539567;