rs200831077

chr22-23767499-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_213720.3(CHCHD10):c.136G>T(p.Ala46Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000691 in 1,556,750 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts 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. A46D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0039 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00035 (5 hom.)
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.69

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008496523).
• BP6: Variant 22-23767499-C-A is Benign according to our data. Variant chr22-23767499-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 473420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00387 (589/152282) while in subpopulation AFR AF= 0.0132 (549/41566). AF 95% confidence interval is 0.0123. There are 7 homozygotes in gnomad4. There are 264 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 585 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHCHD10	NM_213720.3	c.136G>T	p.Ala46Ser	missense_variant	2/4	ENST00000484558.3
CHCHD10	NM_001301339.2	c.136G>T	p.Ala46Ser	missense_variant	2/4
CHCHD10	NR_125755.2	n.181G>T		non_coding_transcript_exon_variant	2/4
CHCHD10	NR_125756.2	n.139+335G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD10	ENST00000484558.3	c.136G>T	p.Ala46Ser	missense_variant	2/4	1	NM_213720.3	P1
CHCHD10	ENST00000401675.7	c.136G>T	p.Ala46Ser	missense_variant	2/4	5
CHCHD10	ENST00000520222.1	c.41+335G>T		intron_variant		3
CHCHD10	ENST00000517886.1	c.83G>T	p.Gly28Val	missense_variant, NMD_transcript_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 585 AN: 152166 Hom.: 6 Cov.: 33

Gnomad AFR AF: 0.0132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000686 AC: 109 AN: 158892 Hom.: 0 AF XY: 0.000482 AC XY: 43 AN XY: 89140

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.000652

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000416

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000154

Gnomad OTH exome AF: 0.000240

GnomAD4 exome AF: 0.000347 AC: 487 AN: 1404468 Hom.: 5 Cov.: 35 AF XY: 0.000275 AC XY: 191 AN XY: 695174

Gnomad4 AFR exome AF: 0.0122

Gnomad4 AMR exome AF: 0.000982

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000617

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000101

Gnomad4 OTH exome AF: 0.00105

GnomAD4 genome AF: 0.00387 AC: 589 AN: 152282 Hom.: 7 Cov.: 33 AF XY: 0.00355 AC XY: 264 AN XY: 74460

Gnomad4 AFR AF: 0.0132

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000886 Hom.: 0

Bravo AF: 0.00430

ESP6500AA AF: 0.00949 AC: 35

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000792 AC: 90

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 28, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Pathogenic	26
Dann	Benign	0.97
DEOGEN2	Benign	0.038	T;T
Eigen	Benign	0.12
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.85	T;T
MetaRNN	Benign	0.0085	T;T
MetaSVM	Benign	-0.73	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.0	N;N
REVEL	Benign	0.15
Sift	Benign	0.048	D;T
Sift4G	Benign	0.061	T;T
Polyphen		1.0	.;D
Vest4		0.54
MVP		0.16
MPC		0.97
ClinPred		0.044	T
GERP RS		2.6
Varity_R		0.15
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200831077; hg19: chr22-24109686;