3-126852728-A-C

Variant names:

• chr3-126852728-A-C
• rs147083615
• NM_032343.3:c.493A>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 16/23 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

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]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
CHCHD6	NM_032343.3	c.493A>C	p.Lys165Gln	missense_variant, splice_region_variant	Exon 5 of 8	ENST00000290913.8	NP_115719.1
CHCHD6	NM_001320610.2	c.496A>C	p.Lys166Gln	missense_variant, splice_region_variant	Exon 5 of 8		NP_001307539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD6	ENST00000290913.8	c.493A>C	p.Lys165Gln	missense_variant, splice_region_variant	Exon 5 of 8	1	NM_032343.3	ENSP00000290913.3

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152132 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000583 AC: 146 AN: 250506 AF XY: 0.000634

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 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.: 5 Cov.: 28 AF XY: 0.000539 AC XY: 391 AN XY: 724850

African (AFR) AF: 0.000839 AC: 28 AN: 33362

American (AMR) AF: 0.000671 AC: 30 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 105 AN: 26076

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39642

South Asian (SAS) AF: 0.000929 AC: 80 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53296

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5744

European-Non Finnish (NFE) AF: 0.000331 AC: 366 AN: 1107310

Other (OTH) AF: 0.00111 AC: 67 AN: 60164

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74426

African (AFR) AF: 0.000120 AC: 5 AN: 41574

American (AMR) AF: 0.000589 AC: 9 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68022

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000825 Hom.: 3

Bravo AF: 0.000495

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000593 AC: 72

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.000771

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.040
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.017	T;T
MetaSVM	Benign	-0.87	T
PhyloP100		3.0
PrimateAI	Benign	0.39	T
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	T
GERP RS		2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.33
Mutation Taster		=79/21	polymorphism

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

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Other links and lift over

dbSNP: rs147083615; hg19: chr3-126571571;