NM_032343.3:c.635C>G

Variant names:

• chr3-126957484-C-G
• rs368713584
• NM_032343.3:c.635C>G

Variant summary

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

The NM_032343.3(CHCHD6):​c.635C>G​(p.Pro212Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,932 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P212L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHCHD6 NM_032343.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.591
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.048593044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD6	NM_032343.3	c.635C>G	p.Pro212Arg	missense_variant	Exon 7 of 8	ENST00000290913.8	NP_115719.1
CHCHD6	NM_001320610.2	c.638C>G	p.Pro213Arg	missense_variant	Exon 7 of 8		NP_001307539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD6	ENST00000290913.8	c.635C>G	p.Pro212Arg	missense_variant	Exon 7 of 8	1	NM_032343.3	ENSP00000290913.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453932 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722498

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.00 AC: 0 AN: 43970

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39142

South Asian (SAS) AF: 0.00 AC: 0 AN: 84492

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52656

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108614

Other (OTH) AF: 0.00 AC: 0 AN: 60070

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.59
DANN	Benign	0.73
DEOGEN2	Benign	0.0036	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.99	T
PhyloP100		0.59
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.35	N;N
REVEL	Benign	0.20
Sift	Benign	0.81	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0010	B;.
Vest4		0.33
MutPred		0.29		Loss of catalytic residue at P212 (P = 0.0286);.;
MVP		0.14
MPC		0.053
ClinPred		0.015	T
GERP RS		-1.8
Varity_R		0.035
gMVP		0.23
Mutation Taster		=99/1	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: rs368713584; hg19: chr3-126676327;