rs769040447

Variant names:

• chr14-49778466-C-G
• rs769040447
• NM_014315.3:c.605C>G

Your query was ambiguous. Multiple possible variants found:

• chr14-49778466-C-G
• chr14-49778466-C-T

Variant summary

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

The NM_014315.3(KLHDC2):​c.605C>G​(p.Thr202Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000758 in 1,319,750 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. T202I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 7.6e-7 (0 hom.)
• Consequence: KLHDC2 NM_014315.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.62
• Publications: 0 publications found

Genes affected

KLHDC2 (HGNC:20231): (kelch domain containing 2) Enables ubiquitin ligase-substrate adaptor activity. Involved in ubiquitin-dependent protein catabolic process via the C-end degron rule pathway. Located in nuclear body and nuclear membrane. Is active in Cul2-RING ubiquitin ligase complex and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014315.3. 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
	KLHDC2	NM_014315.3	MANE Select	c.605C>G	p.Thr202Arg	missense	Exon 6 of 13	NP_055130.1	Q9Y2U9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KLHDC2	ENST00000298307.10	TSL:1 MANE Select	c.605C>G	p.Thr202Arg	missense	Exon 6 of 13	ENSP00000298307.5	Q9Y2U9-1
	KLHDC2	ENST00000554589.5	TSL:5	c.605C>G	p.Thr202Arg	missense	Exon 6 of 12	ENSP00000451439.1	G3V3U8
	KLHDC2	ENST00000913008.1		c.605C>G	p.Thr202Arg	missense	Exon 6 of 11	ENSP00000583067.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 7.58e-7 AC: 1 AN: 1319750 Hom.: 0 Cov.: 26 AF XY: 0.00000152 AC XY: 1 AN XY: 657204

African (AFR) AF: 0.00 AC: 0 AN: 29426

American (AMR) AF: 0.00 AC: 0 AN: 40650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21354

East Asian (EAS) AF: 0.00 AC: 0 AN: 29256

South Asian (SAS) AF: 0.00 AC: 0 AN: 84370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4152

European-Non Finnish (NFE) AF: 9.85e-7 AC: 1 AN: 1015346

Other (OTH) AF: 0.00 AC: 0 AN: 51526

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.079	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		5.6
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.079	T
Polyphen		0.91	P
Vest4		0.77
MutPred		0.33		Gain of solvent accessibility (P = 0.0917)
MVP		0.86
MPC		0.86
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.73
Mutation Taster		=59/41	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: rs769040447; hg19: chr14-50245184;