Variant chr6-125300546-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_016063.3(HDDC2):c.198C>A(p.Asn66Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000346 in 1,613,774 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00036 ( 0 hom. )

Consequence

HDDC2
NM_016063.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.16

Variant links:

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 links:

HDDC2 (HGNC:):

HDDC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
HDDC2	NM_016063.3 linkuse as main transcript	c.198C>A	p.Asn66Lys	missense_variant	2/6	ENST00000398153.7	NP_057147.2	Q7Z4H3-1A0A140VJK7
HDDC2	XM_024446450.2 linkuse as main transcript	c.51C>A	p.Asn17Lys	missense_variant	3/7		XP_024302218.1
HDDC2	XM_047418850.1 linkuse as main transcript	c.198C>A	p.Asn66Lys	missense_variant	2/5		XP_047274806.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDDC2	ENST00000398153.7 linkuse as main transcript	c.198C>A	p.Asn66Lys	missense_variant	2/6	1	NM_016063.3	ENSP00000381220.1		Q7Z4H3-1

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000169

AC:

AN:

249184

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

135202

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.000336

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000363

AC:

531

AN:

1461572

Hom.:

Cov.:

AF XY:

0.000311

AC XY:

226

AN XY:

727096

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000467

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000177

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.000121

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000302

Hom.:

Bravo

AF:

0.000219

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000252

AC:

ESP6500EA

AF:

0.000480

AC:

ExAC

AF:

0.000174

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.198C>A (p.N66K) alteration is located in exon 2 (coding exon 2) of the HDDC2 gene. This alteration results from a C to A substitution at nucleotide position 198, causing the asparagine (N) at amino acid position 66 to be replaced by a lysine (K). 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

0.57

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

T;T;T

Eigen

Benign

0.060

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.85

T;D;D

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Pathogenic

3.3

.;M;.

PrimateAI

Uncertain

0.61

PROVEAN

Uncertain

-4.2

.;D;.

REVEL

Uncertain

0.34

Sift

Uncertain

0.0040

.;D;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.95

.;P;.

Vest4

0.70

MutPred

0.73

Gain of methylation at N66 (P = 0.034);Gain of methylation at N66 (P = 0.034);Gain of methylation at N66 (P = 0.034);

MVP

0.56

MPC

0.33

ClinPred

0.55

GERP RS

0.019

Varity_R

0.80

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over