rs374353973

Positions:

• chr22-23766263-C-G
• chr22-23766263-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The ENST00000484558.3(CHCHD10):​c.274G>C​(p.Ala92Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A92T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 22)
  • Exomes 𝑓: 0.098 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHCHD10 ENST00000484558.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.886

Genes affected

CHCHD10 (HGNC:15559): (coiled-coil-helix-coiled-coil-helix domain containing 10) This gene encodes a mitochondrial protein that is enriched at cristae junctions in the intermembrane space. It may play a role in cristae morphology maintenance or oxidative phosphorylation. Mutations in this gene cause frontotemporal dementia and/or amyotrophic lateral sclerosis-2. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 7 and 19. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025873482).
• BP6: Variant 22-23766263-C-G is Benign according to our data. Variant chr22-23766263-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 1259100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23766263-C-G is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD10	NM_213720.3	c.274G>C	p.Ala92Pro	missense_variant	3/4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2	c.295G>C	p.Ala99Pro	missense_variant	3/4		NP_001288268.1
CHCHD10	NR_125755.2	n.319G>C		non_coding_transcript_exon_variant	3/4
CHCHD10	NR_125756.2	n.152G>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3	c.274G>C	p.Ala92Pro	missense_variant	3/4	1	NM_213720.3	ENSP00000418428	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 116 AN: 79090 Hom.: 0 Cov.: 22 FAILED QC

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00211

Gnomad ASJ AF: 0.00154

Gnomad EAS AF: 0.00249

Gnomad SAS AF: 0.00192

Gnomad FIN AF: 0.00352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.00195

GnomAD3 exomes AF: 0.0831 AC: 6718 AN: 80812 Hom.: 0 AF XY: 0.0786 AC XY: 3548 AN XY: 45124

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.0902

Gnomad EAS exome AF: 0.118

Gnomad SAS exome AF: 0.0793

Gnomad FIN exome AF: 0.0413

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.111

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0980 AC: 63389 AN: 646636 Hom.: 0 Cov.: 24 AF XY: 0.0985 AC XY: 31896 AN XY: 323752

Gnomad4 AFR exome AF: 0.0668

Gnomad4 AMR exome AF: 0.200

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.0980

Gnomad4 SAS exome AF: 0.133

Gnomad4 FIN exome AF: 0.0647

Gnomad4 NFE exome AF: 0.0931

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00147 AC: 116 AN: 79100 Hom.: 0 Cov.: 22 AF XY: 0.00147 AC XY: 56 AN XY: 38030

Gnomad4 AFR AF: 0.000748

Gnomad4 AMR AF: 0.00211

Gnomad4 ASJ AF: 0.00154

Gnomad4 EAS AF: 0.00250

Gnomad4 SAS AF: 0.00193

Gnomad4 FIN AF: 0.00352

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.00193

Alfa AF: 0.0203 Hom.: 0

ExAC AF: 0.000731 AC: 47

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.31
DANN	Benign	0.40
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.28	T;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.65	N;N
REVEL	Benign	0.0060
Sift	Benign	0.32	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.0010	.;B
Vest4		0.12
MutPred		0.30		.;Gain of glycosylation at A92 (P = 0.0011);
MPC		0.66
ClinPred		0.00069	T
GERP RS		-6.6
Varity_R		0.051
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs374353973; hg19: chr22-24108450; COSMIC: COSV59417527; COSMIC: COSV59417527;