chr10-133167492-G-A

Variant names:

• chr10-133167492-G-A
• rs376303101
• NM_152643.8:c.214G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_152643.8(KNDC1):​c.214G>A​(p.Ala72Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000238 in 1,605,384 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. A72S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: KNDC1 NM_152643.8 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.913
• Publications: 2 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07628134).

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.214G>A	p.Ala72Thr	missense	Exon 2 of 30	NP_689856.6
	KNDC1	NM_001347864.2		c.214G>A	p.Ala72Thr	missense	Exon 2 of 3	NP_001334793.1	A0A804HIZ4
	KNDC1	NM_001347865.2		c.214G>A	p.Ala72Thr	missense	Exon 2 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.214G>A	p.Ala72Thr	missense	Exon 2 of 30	ENSP00000304437.3	Q76NI1-1
	KNDC1	ENST00000368571.3	TSL:1	c.214G>A	p.Ala72Thr	missense	Exon 2 of 17	ENSP00000357560.3	Q76NI1-4
	KNDC1	ENST00000946348.1		c.214G>A	p.Ala72Thr	missense	Exon 2 of 31	ENSP00000616407.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 24 AN: 231956 AF XY: 0.000119

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: 0.000134

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.000249 AC: 362 AN: 1453158 Hom.: 0 Cov.: 32 AF XY: 0.000251 AC XY: 181 AN XY: 722076

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 43770

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39374

South Asian (SAS) AF: 0.000284 AC: 24 AN: 84410

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51744

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000299 AC: 332 AN: 1108786

Other (OTH) AF: 0.0000666 AC: 4 AN: 60050

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74366

African (AFR) AF: 0.0000482 AC: 2 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000155 Hom.: 0

Bravo AF: 0.000147

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000827 AC: 10

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.075	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.91
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.12
Sift	Benign	0.18	T
Sift4G	Uncertain	0.013	D
Polyphen		0.81	P
Vest4		0.24
MVP		0.17
MPC		0.18
ClinPred		0.092	T
GERP RS		-1.6
Varity_R		0.053
gMVP		0.42
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376303101; hg19: chr10-134980996; COSMIC: COSV58841942;