NM_152643.8:c.20C>T

Variant names:

• chr10-133160487-C-T
• rs1488194548
• NM_152643.8:c.20C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_152643.8(KNDC1):​c.20C>T​(p.Ala7Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,432,550 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: KNDC1 NM_152643.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.227
• Publications: 0 publications found

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]

ENSG00000294569 (HGNC:):

ACMG classification

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=0.18557304).

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.20C>T	p.Ala7Val	missense	Exon 1 of 30	NP_689856.6
	KNDC1	NM_001347864.2		c.20C>T	p.Ala7Val	missense	Exon 1 of 3	NP_001334793.1	A0A804HIZ4
	KNDC1	NM_001347865.2		c.20C>T	p.Ala7Val	missense	Exon 1 of 4	NP_001334794.1	A0A804HID6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KNDC1	ENST00000304613.8	TSL:1 MANE Select	c.20C>T	p.Ala7Val	missense	Exon 1 of 30	ENSP00000304437.3	Q76NI1-1
	KNDC1	ENST00000368571.3	TSL:1	c.20C>T	p.Ala7Val	missense	Exon 1 of 17	ENSP00000357560.3	Q76NI1-4
	KNDC1	ENST00000946348.1		c.20C>T	p.Ala7Val	missense	Exon 1 of 31	ENSP00000616407.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000149 AC: 3 AN: 201980 AF XY: 0.0000180

Gnomad AFR exome AF: 0.0000946

Gnomad AMR exome AF: 0.0000327

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1432550 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 710902

African (AFR) AF: 0.0000625 AC: 2 AN: 31996

American (AMR) AF: 0.00 AC: 0 AN: 41830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25402

East Asian (EAS) AF: 0.0000263 AC: 1 AN: 37990

South Asian (SAS) AF: 0.00 AC: 0 AN: 82522

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4494

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099506

Other (OTH) AF: 0.00 AC: 0 AN: 59054

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.23
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.067
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.012	D
Polyphen		0.96	D
Vest4		0.38
MutPred		0.22		Loss of disorder (P = 0.0804)
MVP		0.088
MPC		0.20
ClinPred		0.31	T
GERP RS		1.6
PromoterAI		-0.052	Neutral
Varity_R		0.064
gMVP		0.58
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1488194548; hg19: chr10-134973991;