14-49768561-G-C

Variant names:

• chr14-49768561-G-C
• NM_014315.3:c.93G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014315.3(KLHDC2):​c.93G>C​(p.Glu31Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KLHDC2 NM_014315.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.46

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC2	NM_014315.3	c.93G>C	p.Glu31Asp	missense_variant	Exon 1 of 13	ENST00000298307.10	NP_055130.1
KLHDC2	XM_006720094.5	c.93G>C	p.Glu31Asp	missense_variant	Exon 1 of 13		XP_006720157.1
KLHDC2	XM_011536610.2	c.-594G>C		upstream_gene_variant			XP_011534912.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC2	ENST00000298307.10	c.93G>C	p.Glu31Asp	missense_variant	Exon 1 of 13	1	NM_014315.3	ENSP00000298307.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 18, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.93G>C (p.E31D) alteration is located in exon 1 (coding exon 1) of the KLHDC2 gene. This alteration results from a G to C substitution at nucleotide position 93, causing the glutamic acid (E) at amino acid position 31 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;T;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.51	D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0090	D;D;D
Sift4G	Benign	0.072	T;T;T
Polyphen		0.99	D;D;P
Vest4		0.52
MutPred		0.61		Loss of glycosylation at S33 (P = 0.1128);Loss of glycosylation at S33 (P = 0.1128);Loss of glycosylation at S33 (P = 0.1128);
MVP		0.77
MPC		1.0
ClinPred		0.91	D
GERP RS		2.7
Varity_R		0.45
gMVP		0.73

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-50235279;