NM_032343.3:c.62G>A

Variant names:

• chr3-126704374-G-A
• rs748360128
• NM_032343.3:c.62G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_032343.3(CHCHD6):​c.62G>A​(p.Arg21Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R21L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CHCHD6 NM_032343.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38
• 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]

ENSG00000308864 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD6	NM_032343.3	c.62G>A	p.Arg21Gln	missense_variant	Exon 1 of 8	ENST00000290913.8	NP_115719.1
CHCHD6	NM_001320610.2	c.62G>A	p.Arg21Gln	missense_variant	Exon 1 of 8		NP_001307539.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD6	ENST00000290913.8	c.62G>A	p.Arg21Gln	missense_variant	Exon 1 of 8	1	NM_032343.3	ENSP00000290913.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422904 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 704880

African (AFR) AF: 0.00 AC: 0 AN: 32418

American (AMR) AF: 0.00 AC: 0 AN: 38904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25446

East Asian (EAS) AF: 0.00 AC: 0 AN: 37626

South Asian (SAS) AF: 0.00 AC: 0 AN: 81904

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4086

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093740

Other (OTH) AF: 0.0000170 AC: 1 AN: 58816

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.0042	T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.86	T
PhyloP100		2.4
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.16
Sift	Benign	0.059	T;T
Sift4G	Uncertain	0.035	D;D
Polyphen		1.0	D;.
Vest4		0.36
MutPred		0.46		Loss of MoRF binding (P = 0.0462);Loss of MoRF binding (P = 0.0462);
MVP		0.44
MPC		0.36
ClinPred		0.98	D
GERP RS		3.9
PromoterAI		0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.24
gMVP		0.23
Mutation Taster		=68/32	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.63		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.63		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs748360128; hg19: chr3-126423217;