NM_030813.6:c.1086G>A

Variant names:

• chr11-72308597-C-T
• rs146912721
• NM_030813.6:c.1086G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP6_Very_Strong BP7 BS1 BS2

The NM_030813.6(CLPB):​c.1086G>A​(p.Arg362Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00834 in 1,614,034 control chromosomes in the GnomAD database, including 78 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0084 (74 hom.)
• Consequence: CLPB NM_030813.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.24
• Publications: 6 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 -17 ACMG points.

• BP6: Variant 11-72308597-C-T is Benign according to our data. Variant chr11-72308597-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 382370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00729 (1110/152290) while in subpopulation NFE AF = 0.0101 (686/68018). AF 95% confidence interval is 0.00946. There are 4 homozygotes in GnomAd4. There are 560 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030813.6. 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.1086G>A	p.Arg362Arg	synonymous	Exon 9 of 17	NP_110440.1	A0A140VK11
	CLPB	NM_001258392.3	MANE Select	c.996G>A	p.Arg332Arg	synonymous	Exon 8 of 16	NP_001245321.1	Q9H078-2
	CLPB	NM_001258394.3		c.951G>A	p.Arg317Arg	synonymous	Exon 10 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.1086G>A	p.Arg362Arg	synonymous	Exon 9 of 17	ENSP00000294053.3	Q9H078-1
	CLPB	ENST00000538039.6	TSL:2 MANE Select	c.996G>A	p.Arg332Arg	synonymous	Exon 8 of 16	ENSP00000441518.1	Q9H078-2
	CLPB	ENST00000955687.1		c.1059G>A	p.Arg353Arg	synonymous	Exon 8 of 16	ENSP00000625746.1

Frequencies

GnomAD3 genomes AF: 0.00730 AC: 1111 AN: 152172 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0250

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00753 AC: 1893 AN: 251464 AF XY: 0.00760

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00312

Gnomad ASJ exome AF: 0.00198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.0101

Gnomad OTH exome AF: 0.00635

GnomAD4 exome AF: 0.00844 AC: 12343 AN: 1461744 Hom.: 74 Cov.: 31 AF XY: 0.00837 AC XY: 6085 AN XY: 727192

African (AFR) AF: 0.00116 AC: 39 AN: 33480

American (AMR) AF: 0.00320 AC: 143 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 61 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00234 AC: 202 AN: 86256

European-Finnish (FIN) AF: 0.0207 AC: 1105 AN: 53420

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00930 AC: 10345 AN: 1111870

Other (OTH) AF: 0.00737 AC: 445 AN: 60392

GnomAD4 genome AF: 0.00729 AC: 1110 AN: 152290 Hom.: 4 Cov.: 32 AF XY: 0.00752 AC XY: 560 AN XY: 74488

African (AFR) AF: 0.00180 AC: 75 AN: 41566

American (AMR) AF: 0.00163 AC: 25 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4824

European-Finnish (FIN) AF: 0.0250 AC: 265 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0101 AC: 686 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00663 Hom.: 1

Bravo AF: 0.00558

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00894

EpiControl AF: 0.00848

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	3-methylglutaconic aciduria, type VIIB (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		2.2
Mutation Taster		=100/0	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: rs146912721; hg19: chr11-72019641;