14-49779635-C-G

Variant names:

• chr14-49779635-C-G
• rs766932538
• NM_014315.3:c.674C>G

Variant summary

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

The NM_014315.3(KLHDC2):​c.674C>G​(p.Thr225Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T225I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KLHDC2 NM_014315.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.44
• Publications: 1 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.674C>G	p.Thr225Ser	missense	Exon 7 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.674C>G	p.Thr225Ser	missense	Exon 7 of 13	ENSP00000298307.5	Q9Y2U9-1
	KLHDC2	ENST00000893243.1		c.590C>G	p.Thr197Ser	missense	Exon 6 of 12	ENSP00000563302.1
	KLHDC2	ENST00000554589.5	TSL:5	c.674C>G	p.Thr225Ser	missense	Exon 7 of 12	ENSP00000451439.1	G3V3U8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251406 AF XY: 0.00

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.4
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Benign	0.21	T
Sift4G	Benign	0.64	T
Polyphen		1.0	D
Vest4		0.59
MutPred		0.64		Gain of disorder (P = 0.0544)
MVP		0.76
MPC		0.96
ClinPred		0.73	D
GERP RS		5.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.27
gMVP		0.35
Mutation Taster		=46/54	disease causing

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: rs766932538; hg19: chr14-50246353;