NM_014315.3:c.817C>G

Variant names:

• chr14-49780256-C-G
• rs149061228
• NM_014315.3:c.817C>G

Variant summary

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

The NM_014315.3(KLHDC2):​c.817C>G​(p.Leu273Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000695 in 1,613,796 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00072 (0 hom.)
• Consequence: KLHDC2 NM_014315.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20699975).

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.817C>G	p.Leu273Val	missense	Exon 9 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.817C>G	p.Leu273Val	missense	Exon 9 of 13	ENSP00000298307.5	Q9Y2U9-1
	KLHDC2	ENST00000893243.1		c.733C>G	p.Leu245Val	missense	Exon 8 of 12	ENSP00000563302.1
	KLHDC2	ENST00000554589.5	TSL:5	c.817C>G	p.Leu273Val	missense	Exon 9 of 12	ENSP00000451439.1	G3V3U8

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000794

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000414 AC: 104 AN: 251400 AF XY: 0.000390

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000818

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000721 AC: 1054 AN: 1461460 Hom.: 0 Cov.: 30 AF XY: 0.000733 AC XY: 533 AN XY: 727078

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86250

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.000900 AC: 1001 AN: 1111652

Other (OTH) AF: 0.000712 AC: 43 AN: 60376

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000430 AC XY: 32 AN XY: 74482

African (AFR) AF: 0.000240 AC: 10 AN: 41586

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000794 AC: 54 AN: 68022

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000726 Hom.: 1

Bravo AF: 0.000427

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000445 AC: 54

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000763

EpiControl AF: 0.000711

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	0.31
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		1.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.21
Sift	Uncertain	0.012	D
Sift4G	Benign	0.12	T
Polyphen		0.94	P
Vest4		0.63
MVP		0.66
MPC		0.63
ClinPred		0.084	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.52
Mutation Taster		=86/14	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: rs149061228; hg19: chr14-50246974;