chr10-133186204-G-A

Variant names:

• chr10-133186204-G-A
• rs200382676
• NM_152643.8:c.856G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_152643.8(KNDC1):​c.856G>A​(p.Glu286Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,572,904 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0020 (27 hom.)
• Consequence: KNDC1 NM_152643.8 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.350

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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003722906).
• BP6: Variant 10-133186204-G-A is Benign according to our data. Variant chr10-133186204-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3257617.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KNDC1	NM_152643.8	c.856G>A	p.Glu286Lys	missense_variant	Exon 6 of 30	ENST00000304613.8	NP_689856.6
KNDC1	XM_017016858.3	c.856G>A	p.Glu286Lys	missense_variant	Exon 6 of 27		XP_016872347.1
KNDC1	XM_017016859.3	c.856G>A	p.Glu286Lys	missense_variant	Exon 6 of 21		XP_016872348.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNDC1	ENST00000304613.8	c.856G>A	p.Glu286Lys	missense_variant	Exon 6 of 30	1	NM_152643.8	ENSP00000304437.3

Frequencies

GnomAD3 genomes AF: 0.00258 AC: 393 AN: 152108 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00961

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00399

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.00316 AC: 608 AN: 192244 AF XY: 0.00327

Gnomad AFR exome AF: 0.000171

Gnomad AMR exome AF: 0.000277

Gnomad ASJ exome AF: 0.000450

Gnomad EAS exome AF: 0.0000630

Gnomad FIN exome AF: 0.0131

Gnomad NFE exome AF: 0.00417

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00198 AC: 2820 AN: 1420678 Hom.: 27 Cov.: 59 AF XY: 0.00205 AC XY: 1441 AN XY: 702944

Gnomad4 AFR exome AF: 0.000247 AC: 8 AN: 32384

Gnomad4 AMR exome AF: 0.000325 AC: 13 AN: 39944

Gnomad4 ASJ exome AF: 0.000211 AC: 5 AN: 23644

Gnomad4 EAS exome AF: 0.0000257 AC: 1 AN: 38848

Gnomad4 SAS exome AF: 0.0000124 AC: 1 AN: 80712

Gnomad4 FIN exome AF: 0.0129 AC: 639 AN: 49550

Gnomad4 NFE exome AF: 0.00188 AC: 2051 AN: 1091674

Gnomad4 Remaining exome AF: 0.00173 AC: 101 AN: 58354

GnomAD4 genome AF: 0.00258 AC: 393 AN: 152226 Hom.: 4 Cov.: 33 AF XY: 0.00277 AC XY: 206 AN XY: 74416

Gnomad4 AFR AF: 0.000120 AC: 0.000120325 AN: 0.000120325

Gnomad4 AMR AF: 0.000784 AC: 0.000784109 AN: 0.000784109

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000194 AC: 0.00019425 AN: 0.00019425

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00961 AC: 0.00960633 AN: 0.00960633

Gnomad4 NFE AF: 0.00399 AC: 0.00398576 AN: 0.00398576

Gnomad4 OTH AF: 0.000948 AC: 0.000947867 AN: 0.000947867

Alfa AF: 0.00328 Hom.: 4

Bravo AF: 0.00119

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00282 AC: 24

ExAC AF: 0.00318 AC: 382

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KNDC1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.4
DANN	Benign	0.52
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0033	N
LIST_S2	Benign	0.66	T;T
MetaRNN	Benign	0.0037	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.34	N;N
REVEL	Benign	0.015
Sift	Benign	0.74	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0020	B;B
Vest4		0.069
MVP		0.048
MPC		0.21
ClinPred		0.0013	T
GERP RS		-2.9
Varity_R		0.035
gMVP		0.21
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs200382676; hg19: chr10-134999708; COSMIC: COSV58835076;