chr18-47136382-T-C

Position:

• chr18-47136382-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032124.5(HDHD2):​c.58A>G​(p.Ile20Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HDHD2 NM_032124.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0420

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]

ENSG00000267228 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.035080194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDHD2	NM_032124.5	c.58A>G	p.Ile20Val	missense_variant	2/7	ENST00000300605.11	NP_115500.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDHD2	ENST00000300605.11	c.58A>G	p.Ile20Val	missense_variant	2/7	1	NM_032124.5	ENSP00000300605.4
ENSG00000267228	ENST00000588705.1	n.*216A>G		non_coding_transcript_exon_variant	5/6	2		ENSP00000465194.1
ENSG00000267228	ENST00000588705.1	n.*216A>G		3_prime_UTR_variant	5/6	2		ENSP00000465194.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250320 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

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

Oct 25, 2022

The c.58A>G (p.I20V) alteration is located in exon 2 (coding exon 1) of the HDHD2 gene. This alteration results from a A to G substitution at nucleotide position 58, causing the isoleucine (I) at amino acid position 20 to be replaced by a valine (V). 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	Benign	0.082
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	13
DANN	Benign	0.37
DEOGEN2	Benign	0.0075	T;.;T;.;.;T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.80	T;T;T;.;T;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.035	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.58	N;.;.;.;.;.;.
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.17	N;.;.;.;.;.;.
REVEL	Benign	0.033
Sift	Benign	1.0	T;.;.;.;.;.;.
Sift4G	Benign	1.0	T;.;T;.;T;.;T
Polyphen		0.0	B;.;.;.;.;.;.
Vest4		0.19
MutPred		0.45		Gain of catalytic residue at I20 (P = 0.0193);Gain of catalytic residue at I20 (P = 0.0193);Gain of catalytic residue at I20 (P = 0.0193);Gain of catalytic residue at I20 (P = 0.0193);Gain of catalytic residue at I20 (P = 0.0193);Gain of catalytic residue at I20 (P = 0.0193);Gain of catalytic residue at I20 (P = 0.0193);
MVP		0.19
MPC		0.17
ClinPred		0.021	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.061
gMVP		0.27

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

LitVar

Other links and lift over

dbSNP: rs567505755; hg19: chr18-44662753;