chr3-126733218-G-A

Variant names:

• chr3-126733218-G-A
• rs370004672
• NM_032343.3:c.407G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032343.3(CHCHD6):​c.407G>A​(p.Arg136Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R136W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CHCHD6 NM_032343.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.365
• Publications: 2 publications found

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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.018153608).
• BP6: Variant 3-126733218-G-A is Benign according to our data. Variant chr3-126733218-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3144073.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD6	NM_032343.3	c.407G>A	p.Arg136Gln	missense_variant	Exon 4 of 8	ENST00000290913.8	NP_115719.1
CHCHD6	NM_001320610.2	c.407G>A	p.Arg136Gln	missense_variant	Exon 4 of 8		NP_001307539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD6	ENST00000290913.8	c.407G>A	p.Arg136Gln	missense_variant	Exon 4 of 8	1	NM_032343.3	ENSP00000290913.3

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 249298 AF XY: 0.0000222

Gnomad AFR exome AF: 0.000125

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461062 Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9 AN XY: 726764

African (AFR) AF: 0.000120 AC: 4 AN: 33460

American (AMR) AF: 0.0000448 AC: 2 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000900 AC: 10 AN: 1111712

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152332 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74490

African (AFR) AF: 0.000120 AC: 5 AN: 41572

American (AMR) AF: 0.00 AC: 0 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Nov 14, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.22
DANN	Benign	0.45
DEOGEN2	Benign	0.00064	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0067	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.36
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.76	N;N
REVEL	Benign	0.026
Sift	Benign	0.84	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.030	B;.
Vest4		0.031
MVP		0.19
MPC		0.058
ClinPred		0.0094	T
GERP RS		-3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.014
gMVP		0.055
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs370004672; hg19: chr3-126452061; COSMIC: COSV52069618;