Genetic Variant NM_152643.8:c.494G>A (chr10-133183477-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_152643.8(KNDC1):c.494G>A(p.Arg165Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,450,954 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

KNDC1
NM_152643.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.21

Variant links:

Genes affected

KNDC1 (HGNC:29374): (kinase non-catalytic C-lobe domain containing 1) The protein encoded by this gene is a Ras guanine nucleotide exchange factor that appears to negatively regulate dendritic growth in the brain. Knockdown of this gene in senescent umbilical vein endothelial cells partially reversed the senescence, showing that this gene could potentially be targeted by anti-aging therapies. [provided by RefSeq, Dec 2016]

KNDC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNDC1	NM_152643.8 link	c.494G>A	p.Arg165Gln	missense_variant	Exon 4 of 30	ENST00000304613.8	NP_689856.6	Q76NI1-1
KNDC1	XM_017016858.3 link	c.494G>A	p.Arg165Gln	missense_variant	Exon 4 of 27		XP_016872347.1
KNDC1	XM_017016859.3 link	c.494G>A	p.Arg165Gln	missense_variant	Exon 4 of 21		XP_016872348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNDC1	ENST00000304613.8 link	c.494G>A	p.Arg165Gln	missense_variant	Exon 4 of 30	1	NM_152643.8	ENSP00000304437.3		Q76NI1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000875

AC:

AN:

228556

Hom.:

AF XY:

0.00000801

AC XY:

AN XY:

124778

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000352

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1450954

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000831

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.494G>A (p.R165Q) alteration is located in exon 4 (coding exon 4) of the KNDC1 gene. This alteration results from a G to A substitution at nucleotide position 494, causing the arginine (R) at amino acid position 165 to be replaced by a glutamine (Q). 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

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.33

T;.

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.62

MetaRNN

Uncertain

0.73

D;D

MetaSVM

Pathogenic

0.94

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.0

D;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.82

P;D

Vest4

0.56

MutPred

0.40

Gain of helix (P = 0.005);.;

MVP

0.54

MPC

0.65

ClinPred

0.98

GERP RS

4.4

Varity_R

0.52

gMVP

0.91

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over