chr2-112586322-G-T

Variant names:

• chr2-112586322-G-T
• rs1351396503
• NM_032309.4:c.266G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_032309.4(CHCHD5):​c.266G>T​(p.Cys89Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CHCHD5 NM_032309.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.58
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032309.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD5	NM_032309.4	MANE Select	c.266G>T	p.Cys89Phe	missense	Exon 3 of 4	NP_115685.1	Q9BSY4-1
	CHCHD5	NM_001304353.2		c.152G>T	p.Cys51Phe	missense	Exon 3 of 4	NP_001291282.1
	CHCHD5	NM_001304354.2		c.152G>T	p.Cys51Phe	missense	Exon 3 of 4	NP_001291283.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD5	ENST00000324913.10	TSL:1 MANE Select	c.266G>T	p.Cys89Phe	missense	Exon 3 of 4	ENSP00000325655.5	Q9BSY4-1
	CHCHD5	ENST00000409719.1	TSL:2	c.266G>T	p.Cys89Phe	missense	Exon 3 of 3	ENSP00000386994.1	Q9BSY4-2
	CHCHD5	ENST00000454841.5	TSL:2	n.*204G>T		non_coding_transcript_exon	Exon 2 of 3	ENSP00000412731.1	F8WC14

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461886 Hom.: 0 Cov.: 57 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-11	D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.83		Gain of relative solvent accessibility (P = 0.1259)
MVP		0.92
MPC		0.16
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.84
Mutation Taster		=23/77	disease causing

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: rs1351396503; hg19: chr2-113343899;