18-47130304-G-C

Variant names:

• chr18-47130304-G-C
• rs143862755
• NM_032124.5:c.335C>G

Variant summary

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

The NM_032124.5(HDHD2):​c.335C>G​(p.Ala112Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,450,150 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A112V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HDHD2 NM_032124.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.56
• Publications: 5 publications found

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

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_032124.5. 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
	HDHD2	NM_032124.5	MANE Select	c.335C>G	p.Ala112Gly	missense	Exon 4 of 7	NP_115500.1	Q9H0R4-1
	HDHD2	NM_001318765.2		c.65C>G	p.Ala22Gly	missense	Exon 4 of 7	NP_001305694.1	Q9H0R4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDHD2	ENST00000300605.11	TSL:1 MANE Select	c.335C>G	p.Ala112Gly	missense	Exon 4 of 7	ENSP00000300605.4	Q9H0R4-1
	HDHD2	ENST00000588183.5	TSL:1	n.*207C>G		non_coding_transcript_exon	Exon 4 of 7	ENSP00000466602.1	K7EKX8
	HDHD2	ENST00000588183.5	TSL:1	n.*207C>G		3_prime_UTR	Exon 4 of 7	ENSP00000466602.1	K7EKX8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243472 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: 0.00

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1450150 Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1 AN XY: 721560

African (AFR) AF: 0.00 AC: 0 AN: 32892

American (AMR) AF: 0.0000232 AC: 1 AN: 43168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25892

East Asian (EAS) AF: 0.00 AC: 0 AN: 39406

South Asian (SAS) AF: 0.00 AC: 0 AN: 84232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1105484

Other (OTH) AF: 0.00 AC: 0 AN: 59990

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000552

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.068	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.85	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.31
Sift	Benign	0.033	D
Sift4G	Benign	0.093	T
Polyphen		0.018	B
Vest4		0.62
MutPred		0.56		Loss of stability (P = 0.0863)
MVP		0.38
MPC		0.37
ClinPred		0.84	D
GERP RS		6.0
Varity_R		0.68
gMVP		0.81
Mutation Taster		=20/80	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: rs143862755; hg19: chr18-44656675;