rs7938203

Variant names:

• chr11-72329786-C-G
• rs7938203
• NM_030813.6:c.884G>C

Your query was ambiguous. Multiple possible variants found:

• chr11-72329786-C-G
• chr11-72329786-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001258392.3(CLPB):​c.794G>C​(p.Arg265Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,613,810 control chromosomes in the GnomAD database, including 186 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R265R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.018 (91 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (95 hom.)
• Consequence: CLPB NM_001258392.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.25
• Publications: 7 publications found

Genes affected

CLPB (HGNC:30664): (ClpB family mitochondrial disaggregase) This gene belongs to the ATP-ases associated with diverse cellular activities (AAA+) superfamily. Members of this superfamily form ring-shaped homo-hexamers and have highly conserved ATPase domains that are involved in various processes including DNA replication, protein degradation and reactivation of misfolded proteins. All members of this family hydrolyze ATP through their AAA+ domains and use the energy generated through ATP hydrolysis to exert mechanical force on their substrates. In addition to an AAA+ domain, the protein encoded by this gene contains a C-terminal D2 domain, which is characteristic of the AAA+ subfamily of Caseinolytic peptidases to which this protein belongs. It cooperates with Hsp70 in the disaggregation of protein aggregates. Allelic variants of this gene are associated with 3-methylglutaconic aciduria, which causes cataracts and neutropenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]

CLPB Gene-Disease associations (from GenCC):

• 3-methylglutaconic aciduria, type VIIB

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• neutropenia, severe congenital, 9, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002591908).
• BP6: Variant 11-72329786-C-G is Benign according to our data. Variant chr11-72329786-C-G is described in ClinVar as Benign. ClinVar VariationId is 380518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001258392.3. 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
	CLPB	NM_030813.6	MANE Plus Clinical	c.884G>C	p.Arg295Thr	missense	Exon 7 of 17	NP_110440.1	A0A140VK11
	CLPB	NM_001258392.3	MANE Select	c.794G>C	p.Arg265Thr	missense	Exon 6 of 16	NP_001245321.1	Q9H078-2
	CLPB	NM_001258394.3		c.749G>C	p.Arg250Thr	missense	Exon 8 of 18	NP_001245323.1	Q9H078-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CLPB	ENST00000294053.9	TSL:1 MANE Plus Clinical	c.884G>C	p.Arg295Thr	missense	Exon 7 of 17	ENSP00000294053.3	Q9H078-1
	CLPB	ENST00000538039.6	TSL:2 MANE Select	c.794G>C	p.Arg265Thr	missense	Exon 6 of 16	ENSP00000441518.1	Q9H078-2
	CLPB	ENST00000955687.1		c.857G>C	p.Arg286Thr	missense	Exon 6 of 16	ENSP00000625746.1

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2798 AN: 152118 Hom.: 92 Cov.: 32

Gnomad AFR AF: 0.0644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00504

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00459 AC: 1154 AN: 251210 AF XY: 0.00338

Gnomad AFR exome AF: 0.0655

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00191 AC: 2795 AN: 1461574 Hom.: 95 Cov.: 30 AF XY: 0.00168 AC XY: 1221 AN XY: 727106

African (AFR) AF: 0.0711 AC: 2378 AN: 33448

American (AMR) AF: 0.00210 AC: 94 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5764

European-Non Finnish (NFE) AF: 0.0000747 AC: 83 AN: 1111834

Other (OTH) AF: 0.00363 AC: 219 AN: 60382

GnomAD4 genome AF: 0.0184 AC: 2796 AN: 152236 Hom.: 91 Cov.: 32 AF XY: 0.0174 AC XY: 1295 AN XY: 74446

African (AFR) AF: 0.0642 AC: 2665 AN: 41520

American (AMR) AF: 0.00503 AC: 77 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68012

Other (OTH) AF: 0.0156 AC: 33 AN: 2116

Alfa AF: 0.00273 Hom.: 11

Bravo AF: 0.0212

ESP6500AA AF: 0.0611 AC: 269

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00562 AC: 683

Asia WGS AF: 0.00260 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	3-methylglutaconic aciduria, type VIIB (1)
-	-	1	CLPB-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	20
DANN	Benign	0.93
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.061
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0050	N
PhyloP100		2.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.11
Sift	Benign	0.18	T
Sift4G	Benign	0.38	T
Polyphen		0.0030	B
Vest4		0.23
MVP		0.68
MPC		0.57
ClinPred		0.010	T
GERP RS		5.4
Varity_R		0.059
gMVP		0.38
Mutation Taster		=93/7	polymorphism (auto)

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: rs7938203; hg19: chr11-72040830;