18-47115246-T-G

Position:

• chr18-47115246-T-G

Variant summary

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

The NM_032124.5(HDHD2):​c.498A>C​(p.Leu166Phe) variant causes a missense change involving the alteration of a non-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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HDHD2 NM_032124.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.272

Genes affected

HDHD2 (HGNC:25364): (haloacid dehalogenase like hydrolase domain containing 2) Enables enzyme binding activity. Predicted to be involved in dephosphorylation. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

HDHD2 (HGNC:):

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/exons	MANE	Protein	UniProt
HDHD2	NM_032124.5	c.498A>C	p.Leu166Phe	missense_variant	5/7	ENST00000300605.11	NP_115500.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDHD2	ENST00000300605.11	c.498A>C	p.Leu166Phe	missense_variant	5/7	1	NM_032124.5	ENSP00000300605.4

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

The c.498A>C (p.L166F) alteration is located in exon 5 (coding exon 4) of the HDHD2 gene. This alteration results from a A to C substitution at nucleotide position 498, causing the leucine (L) at amino acid position 166 to be replaced by a phenylalanine (F). 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	0.62
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	0.089
Eigen_PC	Benign	-0.089
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.5	M;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		0.97	D;.
Vest4		0.76
MutPred		0.67		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.36
MPC		0.84
ClinPred		1.0	D
GERP RS		-4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr18-44641617;