Variant 3-126852728-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_032343.3(CHCHD6):c.493A>C(p.Lys165Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000506 in 1,608,622 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 5 hom. )

Consequence

CHCHD6
NM_032343.3 missense, splice_region

Scores

Splicing: ADA: 0.00004655

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.00

Variant links:

Genes affected

CHCHD6 (HGNC:28184): (coiled-coil-helix-coiled-coil-helix domain containing 6) Involved in cellular response to DNA damage stimulus and cristae formation. Located in cytosol and mitochondrial inner membrane. Part of MICOS complex. [provided by Alliance of Genome Resources, Apr 2022]

CHCHD6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017124116).

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHCHD6	NM_032343.3 linkuse as main transcript	c.493A>C	p.Lys165Gln	missense_variant, splice_region_variant	5/8	ENST00000290913.8
CHCHD6	NM_001320610.2 linkuse as main transcript	c.496A>C	p.Lys166Gln	missense_variant, splice_region_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD6	ENST00000290913.8 linkuse as main transcript	c.493A>C	p.Lys165Gln	missense_variant, splice_region_variant	5/8	1	NM_032343.3	P1

Frequencies

GnomAD3 genomes

AF:

0.000434

AC:

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000583

AC:

146

AN:

250506

Hom.:

AF XY:

0.000634

AC XY:

AN XY:

135560

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.000492

Gnomad ASJ exome

AF:

0.00328

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000982

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000459

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000514

AC:

749

AN:

1456372

Hom.:

Cov.:

AF XY:

0.000539

AC XY:

391

AN XY:

724850

show subpopulations

Gnomad4 AFR exome

AF:

0.000839

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00403

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000929

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000331

Gnomad4 OTH exome

AF:

0.00111

GnomAD4 genome

AF:

0.000427

AC:

AN:

152250

Hom.:

Cov.:

AF XY:

0.000497

AC XY:

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000946

Hom.:

Bravo

AF:

0.000495

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000593

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.000771

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

Oct 18, 2021

The c.493A>C (p.K165Q) alteration is located in exon 5 (coding exon 5) of the CHCHD6 gene. This alteration results from a A to C substitution at nucleotide position 493, causing the lysine (K) at amino acid position 165 to be replaced by a glutamine (Q). 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

0.19

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.030

T;.

Eigen

Benign

0.11

Eigen_PC

Benign

0.040

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.69

T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-0.87

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.5

N;N

REVEL

Benign

0.15

Sift

Benign

0.050

D;D

Sift4G

Benign

0.069

T;T

Polyphen

1.0

D;.

Vest4

0.38

MVP

0.36

MPC

0.13

ClinPred

0.049

GERP RS

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.33

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000047

dbscSNV1_RF

Benign

0.048

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

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