Genetic Variant NM_032309.4:c.128A>G (chr2-112586099-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6_Moderate

The NM_032309.4(CHCHD5):c.128A>G(p.Gln43Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000159 in 1,571,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000095 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

CHCHD5
NM_032309.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.72

Publications

3 publications found

Variant links:

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]

CHCHD5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.054465115).

BP6

Variant 2-112586099-A-G is Benign according to our data. Variant chr2-112586099-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3144069.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHCHD5	NM_032309.4	MANE Select	c.128A>G	p.Gln43Arg	missense	Exon 2 of 4	NP_115685.1	Q9BSY4-1
CHCHD5	NM_001304353.2		c.14A>G	p.Gln5Arg	missense	Exon 2 of 4	NP_001291282.1
CHCHD5	NM_001304354.2		c.14A>G	p.Gln5Arg	missense	Exon 2 of 4	NP_001291283.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHCHD5	ENST00000324913.10	TSL:1 MANE Select	c.128A>G	p.Gln43Arg	missense	Exon 2 of 4	ENSP00000325655.5	Q9BSY4-1
CHCHD5	ENST00000409719.1	TSL:2	c.128A>G	p.Gln43Arg	missense	Exon 2 of 3	ENSP00000386994.1	Q9BSY4-2
CHCHD5	ENST00000454841.5	TSL:2	n.128A>G		non_coding_transcript_exon	Exon 2 of 3	ENSP00000412731.1	F8WC14

Frequencies

GnomAD3 genomes

AF:

0.0000949

AC:

AN:

147502

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000319

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000488

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251330

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00

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:

0.00000772

AC:

AN:

1424052

Hom.:

Cov.:

AF XY:

0.00000707

AC XY:

AN XY:

707620

show subpopulations

African (AFR)

AF:

0.000247

AC:

AN:

32380

American (AMR)

AF:

0.0000230

AC:

AN:

43450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24878

East Asian (EAS)

AF:

0.00

AC:

AN:

36964

South Asian (SAS)

AF:

0.00

AC:

AN:

85902

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5586

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087000

Other (OTH)

AF:

0.0000346

AC:

AN:

57854

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000948

AC:

AN:

147634

Hom.:

Cov.:

AF XY:

0.0000555

AC XY:

AN XY:

72088

show subpopulations

African (AFR)

AF:

0.000318

AC:

AN:

40824

American (AMR)

AF:

0.00

AC:

AN:

14950

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3398

East Asian (EAS)

AF:

0.00

AC:

AN:

4628

South Asian (SAS)

AF:

0.00

AC:

AN:

4398

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

66522

Other (OTH)

AF:

0.000483

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.71

CADD

Benign

6.7

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0050

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.61

M_CAP

Benign

0.0015

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.075

PhyloP100

1.7

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.80

REVEL

Benign

0.012

Sift

Benign

0.59

Polyphen

0.0

Vest4

0.26

MutPred

0.21

Gain of MoRF binding (P = 0.0127)

MVP

0.21

MPC

0.018

ClinPred

0.0051

GERP RS

0.73

Varity_R

0.033

gMVP

0.46

Mutation Taster

=72/28

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over