Genetic Variant KNDC1:p.Arg165Trp (chr10-133183476-C-T) – 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.493C>T(p.Arg165Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000274 in 1,603,398 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 1 hom. )

Consequence

KNDC1
NM_152643.8 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.292

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:

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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.493C>T	p.Arg165Trp	missense_variant	Exon 4 of 30	ENST00000304613.8	NP_689856.6	Q76NI1-1
KNDC1	XM_017016858.3 link	c.493C>T	p.Arg165Trp	missense_variant	Exon 4 of 27		XP_016872347.1
KNDC1	XM_017016859.3 link	c.493C>T	p.Arg165Trp	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.493C>T	p.Arg165Trp	missense_variant	Exon 4 of 30	1	NM_152643.8	ENSP00000304437.3		Q76NI1-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000144

AC:

AN:

229026

Hom.:

AF XY:

0.0000799

AC XY:

AN XY:

125084

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00100

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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

AF:

0.0000262

AC:

AN:

1451138

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

721164

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000846

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000416

ExAC

AF:

0.000141

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

D;.

Eigen

Benign

0.072

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.21

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.75

MetaRNN

Uncertain

0.60

D;D

MetaSVM

Pathogenic

0.93

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.9

D;D

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.70

MVP

0.49

MPC

0.70

ClinPred

0.71

GERP RS

2.3

Varity_R

0.75

gMVP

0.94

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over