rs551521196

Variant names:

• chr22-23767535-G-A
• rs551521196
• NM_213720.3:c.100C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_213720.3(CHCHD10):​c.100C>T​(p.Pro34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,451,942 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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. P34L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (17 hom.)
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.56
• Publications: 30 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• frontotemporal dementia and/or amyotrophic lateral sclerosis 2

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

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011065036).
• BP6: Variant 22-23767535-G-A is Benign according to our data. Variant chr22-23767535-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 204291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 349 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	NM_213720.3	MANE Select	c.100C>T	p.Pro34Ser	missense	Exon 2 of 4	NP_998885.1	Q8WYQ3
	CHCHD10	NM_001301339.2		c.100C>T	p.Pro34Ser	missense	Exon 2 of 4	NP_001288268.1	B5MBW9
	CHCHD10	NR_125755.2		n.145C>T		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	ENST00000484558.3	TSL:1 MANE Select	c.100C>T	p.Pro34Ser	missense	Exon 2 of 4	ENSP00000418428.3	Q8WYQ3
	CHCHD10	ENST00000878118.1		c.163C>T	p.Pro55Ser	missense	Exon 2 of 4	ENSP00000548177.1
	CHCHD10	ENST00000878120.1		c.100C>T	p.Pro34Ser	missense	Exon 2 of 4	ENSP00000548179.1

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 349 AN: 152156 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00277 AC: 176 AN: 63606 AF XY: 0.00249

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.00501

Gnomad OTH exome AF: 0.000619

GnomAD4 exome AF: 0.00426 AC: 5542 AN: 1299678 Hom.: 17 Cov.: 35 AF XY: 0.00408 AC XY: 2603 AN XY: 638006

African (AFR) AF: 0.000658 AC: 17 AN: 25824

American (AMR) AF: 0.00109 AC: 23 AN: 21098

Ashkenazi Jewish (ASJ) AF: 0.0000917 AC: 2 AN: 21820

East Asian (EAS) AF: 0.00 AC: 0 AN: 29182

South Asian (SAS) AF: 0.0000429 AC: 3 AN: 69964

European-Finnish (FIN) AF: 0.00248 AC: 96 AN: 38678

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3762

European-Non Finnish (NFE) AF: 0.00507 AC: 5251 AN: 1036030

Other (OTH) AF: 0.00281 AC: 150 AN: 53320

GnomAD4 genome AF: 0.00229 AC: 349 AN: 152264 Hom.: 1 Cov.: 33 AF XY: 0.00195 AC XY: 145 AN XY: 74446

African (AFR) AF: 0.000962 AC: 40 AN: 41568

American (AMR) AF: 0.00124 AC: 19 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00381 AC: 259 AN: 67988

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00180 Hom.: 2

Bravo AF: 0.00235

ExAC AF: 0.00113 AC: 95

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Autosomal dominant mitochondrial myopathy with exercise intolerance (1)
-	-	1	CHCHD10-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Lower motor neuron syndrome with late-adult onset (1)
-	-	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)
-	-	-	Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Benign	0.022	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.62	T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.6
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.62
Sift	Benign	0.24	T
Sift4G	Benign	0.14	T
Polyphen		0.056	B
Vest4		0.36
MVP		0.13
MPC		0.51
ClinPred		0.012	T
GERP RS		1.3
PromoterAI		-0.0045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.070
gMVP		0.36
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs551521196; hg19: chr22-24109722;