Genetic Variant NM_152643.8:c.646C>T (chr10-133185994-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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. 12/21 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. R216L) has been classified 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

Publications

2 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152643.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNDC1	NM_152643.8	MANE Select	c.646C>T	p.Arg216Trp	missense	Exon 6 of 30	NP_689856.6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KNDC1	ENST00000304613.8	TSL:1 MANE Select	c.646C>T	p.Arg216Trp	missense	Exon 6 of 30	ENSP00000304437.3	Q76NI1-1
KNDC1	ENST00000368571.3	TSL:1	c.646C>T	p.Arg216Trp	missense	Exon 6 of 17	ENSP00000357560.3	Q76NI1-4
KNDC1	ENST00000946348.1		c.646C>T	p.Arg216Trp	missense	Exon 6 of 31	ENSP00000616407.1

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

GnomAD2 exomes

AF:

0.00000940

AC:

AN:

212708

AF XY:

0.00000858

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000325

AC:

AN:

1446596

Hom.:

Cov.:

AF XY:

0.0000334

AC XY:

AN XY:

718118

show subpopulations

African (AFR)

AF:

0.0000600

AC:

AN:

33348

American (AMR)

AF:

0.0000233

AC:

AN:

42850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25652

East Asian (EAS)

AF:

0.00

AC:

AN:

39162

South Asian (SAS)

AF:

0.00

AC:

AN:

83554

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5482

European-Non Finnish (NFE)

AF:

0.0000380

AC:

AN:

1106342

Other (OTH)

AF:

0.0000334

AC:

AN:

59810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000466

AC:

AN:

150166

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73228

show subpopulations

African (AFR)

AF:

0.0000246

AC:

AN:

40682

American (AMR)

AF:

0.000265

AC:

AN:

15106

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3438

East Asian (EAS)

AF:

0.00

AC:

AN:

5078

South Asian (SAS)

AF:

0.000211

AC:

AN:

4742

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67452

Other (OTH)

AF:

0.00

AC:

AN:

2054

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000168

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.075

LIST_S2

Benign

0.80

M_CAP

Benign

0.022

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

PhyloP100

0.62

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.085

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

1.0

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

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over