6-125300562-T-C

Position:

• chr6-125300562-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016063.3(HDDC2):​c.182A>G​(p.Lys61Arg) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: HDDC2 NM_016063.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.077972054).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDDC2	NM_016063.3	c.182A>G	p.Lys61Arg	missense_variant	2/6	ENST00000398153.7	NP_057147.2
HDDC2	XM_024446450.2	c.35A>G	p.Lys12Arg	missense_variant	3/7		XP_024302218.1
HDDC2	XM_047418850.1	c.182A>G	p.Lys61Arg	missense_variant	2/5		XP_047274806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDDC2	ENST00000398153.7	c.182A>G	p.Lys61Arg	missense_variant	2/6	1	NM_016063.3	ENSP00000381220.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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.182A>G (p.K61R) alteration is located in exon 2 (coding exon 2) of the HDDC2 gene. This alteration results from a A to G substitution at nucleotide position 182, causing the lysine (K) at amino acid position 61 to be replaced by an arginine (R). 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	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T;T;T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.63	.;N;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.63	.;N;.
REVEL	Benign	0.024
Sift	Benign	0.50	.;T;.
Sift4G	Benign	0.46	T;T;T
Polyphen		0.0010	.;B;.
Vest4		0.060
MutPred		0.35		Loss of catalytic residue at M56 (P = 0.0353);Loss of catalytic residue at M56 (P = 0.0353);Loss of catalytic residue at M56 (P = 0.0353);
MVP		0.39
MPC		0.12
ClinPred		0.18	T
GERP RS		0.74
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.16
gMVP		0.29

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: rs1313791542; hg19: chr6-125621708;