2-112586316-T-G

Position:

• chr2-112586316-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032309.4(CHCHD5):​c.260T>G​(p.Leu87Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CHCHD5 NM_032309.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.09

Genes affected

CHCHD5 (HGNC:17840): (coiled-coil-helix-coiled-coil-helix domain containing 5) Predicted to be located in mitochondrial intermembrane space. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD5	NM_032309.4	c.260T>G	p.Leu87Arg	missense_variant	3/4	ENST00000324913.10	NP_115685.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHCHD5	ENST00000324913.10	c.260T>G	p.Leu87Arg	missense_variant	3/4	1	NM_032309.4	ENSP00000325655	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251316 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461888 Hom.: 0 Cov.: 55 AF XY: 0.00000275 AC XY: 2 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2023

The c.260T>G (p.L87R) alteration is located in exon 3 (coding exon 3) of the CHCHD5 gene. This alteration results from a T to G substitution at nucleotide position 260, causing the leucine (L) at amino acid position 87 to be replaced by an arginine (R). 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	Uncertain	0.55
BayesDel_addAF	Benign	-0.035	T
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T;.
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.73	D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;D
Polyphen		1.0	D;.
Vest4		0.75
MutPred		0.57		Gain of MoRF binding (P = 0.0158);Gain of MoRF binding (P = 0.0158);
MVP		0.78
MPC		0.16
ClinPred		0.74	D
GERP RS		4.5
Varity_R		0.49
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs753637909; hg19: chr2-113343893;