rs111527940

Variant names:

• chr22-23767401-C-G
• rs111527940
• NM_213720.3:c.234G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-23767401-C-G
• chr22-23767401-C-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 2P and 7B. PM2 BP4_Strong BP6_Moderate BP7

The NM_213720.3(CHCHD10):​c.234G>C​(p.Ser78Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,456,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. S78S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHCHD10 NM_213720.3 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.35
• Publications: 6 publications found

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]

CHCHD10 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant mitochondrial myopathy with exercise intolerance

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• frontotemporal dementia and/or amyotrophic lateral sclerosis 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• lower motor neuron syndrome with late-adult onset

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.013).
• BP6: Variant 22-23767401-C-G is Benign according to our data. Variant chr22-23767401-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1900233.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.35 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213720.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	NM_213720.3	MANE Select	c.234G>C	p.Ser78Ser	synonymous	Exon 2 of 4	NP_998885.1
	CHCHD10	NM_001301339.2		c.234G>C	p.Ser78Ser	synonymous	Exon 2 of 4	NP_001288268.1
	CHCHD10	NR_125755.2		n.279G>C		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	ENST00000484558.3	TSL:1 MANE Select	c.234G>C	p.Ser78Ser	synonymous	Exon 2 of 4	ENSP00000418428.3
	CHCHD10	ENST00000401675.7	TSL:5	c.234G>C	p.Ser78Ser	synonymous	Exon 2 of 4	ENSP00000384973.3
	CHCHD10	ENST00000517886.1	TSL:3	n.181G>C		non_coding_transcript_exon	Exon 2 of 4	ENSP00000429976.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000424 AC: 1 AN: 235754 AF XY: 0.00000770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000206 AC: 3 AN: 1456176 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 724184

African (AFR) AF: 0.00 AC: 0 AN: 33318

American (AMR) AF: 0.0000225 AC: 1 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.00 AC: 0 AN: 85562

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4184

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110954

Other (OTH) AF: 0.0000167 AC: 1 AN: 60006

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Lower motor neuron syndrome with late-adult onset;C4014648:Frontotemporal dementia and/or amyotrophic lateral sclerosis 2;C4015513:Autosomal dominant mitochondrial myopathy with exercise intolerance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_noAF	Benign	-0.54
CADD	Benign	4.6
DANN	Benign	0.82
PhyloP100		-2.3
PromoterAI		-0.014	Neutral

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: rs111527940; hg19: chr22-24109588;