chr10-133160487-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_152643.8(KNDC1):​c.20C>A​(p.Ala7Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KNDC1 NM_152643.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3373103).

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>A	p.Ala7Asp	missense	Exon 1 of 30	NP_689856.6
	KNDC1	NM_001347864.2		c.20C>A	p.Ala7Asp	missense	Exon 1 of 3	NP_001334793.1	A0A804HIZ4
	KNDC1	NM_001347865.2		c.20C>A	p.Ala7Asp	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>A	p.Ala7Asp	missense	Exon 1 of 30	ENSP00000304437.3	Q76NI1-1
	KNDC1	ENST00000368571.3	TSL:1	c.20C>A	p.Ala7Asp	missense	Exon 1 of 17	ENSP00000357560.3	Q76NI1-4
	KNDC1	ENST00000946348.1		c.20C>A	p.Ala7Asp	missense	Exon 1 of 31	ENSP00000616407.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432550 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 710902

African (AFR) AF: 0.00 AC: 0 AN: 31996

American (AMR) AF: 0.00 AC: 0 AN: 41828

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

East Asian (EAS) AF: 0.00 AC: 0 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: 9.09e-7 AC: 1 AN: 1099508

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

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.23
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.051
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.96	D
Vest4		0.55
MutPred		0.22		Gain of relative solvent accessibility (P = 0.0082)
MVP		0.14
MPC		0.31
ClinPred		0.43	T
GERP RS		1.6
PromoterAI		0.016	Neutral
Varity_R		0.27
gMVP		0.77
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;