chr6-125298751-T-A

Position:

• chr6-125298751-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016063.3(HDDC2):​c.272A>T​(p.Asp91Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HDDC2 NM_016063.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.95

Genes affected

HDDC2 (HGNC:21078): (HD domain containing 2) Predicted to enable 5'-deoxynucleotidase activity. Predicted to be involved in dephosphorylation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

HDDC2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.821

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDDC2	NM_016063.3	c.272A>T	p.Asp91Val	missense_variant	3/6	ENST00000398153.7	NP_057147.2
HDDC2	XM_024446450.2	c.125A>T	p.Asp42Val	missense_variant	4/7		XP_024302218.1
HDDC2	XM_047418850.1	c.272A>T	p.Asp91Val	missense_variant	3/5		XP_047274806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDDC2	ENST00000398153.7	c.272A>T	p.Asp91Val	missense_variant	3/6	1	NM_016063.3	ENSP00000381220.1

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

Dec 14, 2023

The c.272A>T (p.D91V) alteration is located in exon 3 (coding exon 3) of the HDDC2 gene. This alteration results from a A to T substitution at nucleotide position 272, causing the aspartic acid (D) at amino acid position 91 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	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T;T;T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.071	D
MetaRNN	Pathogenic	0.82	D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Pathogenic	3.5	.;M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.2	.;D;.
REVEL	Uncertain	0.54
Sift	Benign	0.052	.;T;.
Sift4G	Uncertain	0.033	D;T;D
Polyphen		0.88	.;P;.
Vest4		0.94
MutPred		0.41		Loss of disorder (P = 0.0359);Loss of disorder (P = 0.0359);Loss of disorder (P = 0.0359);
MVP		0.71
MPC		0.75
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr6-125619897;