2-112586316-T-A

Variant names:

• chr2-112586316-T-A
• rs753637909
• NM_032309.4:c.260T>A

Variant summary

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

The NM_032309.4(CHCHD5):​c.260T>A​(p.Leu87Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. L87P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHCHD5 NM_032309.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.09
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785

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.260T>A	p.Leu87Gln	missense	Exon 3 of 4	NP_115685.1	Q9BSY4-1
	CHCHD5	NM_001304353.2		c.146T>A	p.Leu49Gln	missense	Exon 3 of 4	NP_001291282.1
	CHCHD5	NM_001304354.2		c.146T>A	p.Leu49Gln	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.260T>A	p.Leu87Gln	missense	Exon 3 of 4	ENSP00000325655.5	Q9BSY4-1
	CHCHD5	ENST00000409719.1	TSL:2	c.260T>A	p.Leu87Gln	missense	Exon 3 of 3	ENSP00000386994.1	Q9BSY4-2
	CHCHD5	ENST00000454841.5	TSL:2	n.*198T>A		non_coding_transcript_exon	Exon 2 of 3	ENSP00000412731.1	F8WC14

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 55

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.1
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.51		Gain of disorder (P = 0.0357)
MVP		0.79
MPC		0.15
ClinPred		0.99	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.69
Mutation Taster		=44/56	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: rs753637909; hg19: chr2-113343893;