Variant 10-133185994-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152643.8(KNDC1):c.646C>T(p.Arg216Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000338 in 1,596,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

KNDC1
NM_152643.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.619

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13407603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
KNDC1	NM_152643.8 linkuse as main transcript	c.646C>T	p.Arg216Trp	missense_variant	6/30	ENST00000304613.8	NP_689856.6
KNDC1	XM_017016858.3 linkuse as main transcript	c.646C>T	p.Arg216Trp	missense_variant	6/27		XP_016872347.1
KNDC1	XM_017016859.3 linkuse as main transcript	c.646C>T	p.Arg216Trp	missense_variant	6/21		XP_016872348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KNDC1	ENST00000304613.8 linkuse as main transcript	c.646C>T	p.Arg216Trp	missense_variant	6/30	1	NM_152643.8	ENSP00000304437	P1	Q76NI1-1

Frequencies

GnomAD3 genomes

AF:

0.0000466

AC:

AN:

150166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000265

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000211

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000325

AC:

AN:

1446596

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

718118

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.0000233

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:

0.0000380

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.0000466

AC:

AN:

150166

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73228

show subpopulations

Gnomad4 AFR

AF:

0.0000246

Gnomad4 AMR

AF:

0.000265

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000211

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ExAC

AF:

0.0000168

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2022

The c.646C>T (p.R216W) alteration is located in exon 6 (coding exon 6) of the KNDC1 gene. This alteration results from a C to T substitution at nucleotide position 646, causing the arginine (R) at amino acid position 216 to be replaced by a tryptophan (W). 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

0.16

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.6

D;D

REVEL

Benign

0.085

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.23

MutPred

0.27

Gain of helix (P = 0.005);.;

MVP

0.20

MPC

0.30

ClinPred

0.83

GERP RS

-1.5

Varity_R

0.15

gMVP

0.36

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