rs143097446

Variant names:

• chr11-72372993-C-T
• rs143097446
• NM_030813.6:c.668G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_030813.6(CLPB):​c.668G>A​(p.Ser223Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,614,066 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (53 hom.)
• Consequence: CLPB NM_030813.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.22
• Publications: 10 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=0.0041360855).
• BP6: Variant 11-72372993-C-T is Benign according to our data. Variant chr11-72372993-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00445 (677/152248) while in subpopulation NFE AF = 0.00739 (503/68022). AF 95% confidence interval is 0.00686. There are 3 homozygotes in GnomAd4. There are 305 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.668G>A	p.Ser223Asn	missense	Exon 5 of 17	NP_110440.1	A0A140VK11
	CLPB	NM_001258392.3	MANE Select	c.646+7288G>A		intron	N/A	NP_001245321.1	Q9H078-2
	CLPB	NM_001258394.3		c.533G>A	p.Ser178Asn	missense	Exon 6 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.668G>A	p.Ser223Asn	missense	Exon 5 of 17	ENSP00000294053.3	Q9H078-1
	CLPB	ENST00000538039.6	TSL:2 MANE Select	c.646+7288G>A		intron	N/A	ENSP00000441518.1	Q9H078-2
	CLPB	ENST00000543042.6	TSL:2	c.668G>A	p.Ser223Asn	missense	Exon 5 of 16	ENSP00000439746.2	A0A2U3TZY2

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 677 AN: 152130 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00262

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00739

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00461 AC: 1157 AN: 251248 AF XY: 0.00450

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00702

Gnomad NFE exome AF: 0.00778

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00707 AC: 10328 AN: 1461818 Hom.: 53 Cov.: 30 AF XY: 0.00684 AC XY: 4976 AN XY: 727220

African (AFR) AF: 0.00128 AC: 43 AN: 33480

American (AMR) AF: 0.00177 AC: 79 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26136

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

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86258

European-Finnish (FIN) AF: 0.00590 AC: 315 AN: 53412

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.00860 AC: 9568 AN: 1111950

Other (OTH) AF: 0.00474 AC: 286 AN: 60390

GnomAD4 genome AF: 0.00445 AC: 677 AN: 152248 Hom.: 3 Cov.: 32 AF XY: 0.00410 AC XY: 305 AN XY: 74438

African (AFR) AF: 0.00135 AC: 56 AN: 41536

American (AMR) AF: 0.00262 AC: 40 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00565 AC: 60 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00739 AC: 503 AN: 68022

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00603 Hom.: 6

Bravo AF: 0.00423

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.00804 AC: 31

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00676 AC: 58

ExAC AF: 0.00451 AC: 548

EpiCase AF: 0.00692

EpiControl AF: 0.00782

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	3-methylglutaconic aciduria, type VIIB (1)
-	-	1	3-methylglutaconic aciduria, type VIIB;C5676954:Neutropenia, severe congenital, 9, autosomal dominant;C5676967:3-methylglutaconic aciduria, type VIIA (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.67
DEOGEN2	Benign	0.028	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.0041	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.2
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.018
Sift	Benign	0.037	D
Sift4G	Benign	0.23	T
Polyphen		0.019	B
Vest4		0.35
MVP		0.54
MPC		0.36
ClinPred		0.0048	T
GERP RS		2.2
Varity_R		0.051
gMVP		0.37
Mutation Taster		=95/5	polymorphism

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: rs143097446; hg19: chr11-72084037; COSMIC: COSV53631255;