rs114173613

Variant names:

• chr16-28904503-C-T
• rs114173613
• NM_024816.3:c.*440G>A

Variant summary

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

The NM_024816.3(RABEP2):​c.*440G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,484,182 control chromosomes in the GnomAD database, including 390 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (68 hom., cov: 33)
  • Exomes 𝑓: 0.0080 (322 hom.)
• Consequence: RABEP2 NM_024816.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.106
• Publications: 2 publications found

Genes affected

RABEP2 (HGNC:24817): (rabaptin, RAB GTPase binding effector protein 2) Predicted to enable GTPase activator activity and growth factor activity. Involved in regulation of cilium assembly. Located in cytosol; intracellular membrane-bounded organelle; and microtubule organizing center. [provided by Alliance of Genome Resources, Apr 2022]

ATP2A1 (HGNC:811): (ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1) This gene encodes one of the SERCA Ca(2+)-ATPases, which are intracellular pumps located in the sarcoplasmic or endoplasmic reticula of muscle cells. This enzyme catalyzes the hydrolysis of ATP coupled with the translocation of calcium from the cytosol to the sarcoplasmic reticulum lumen, and is involved in muscular excitation and contraction. Mutations in this gene cause some autosomal recessive forms of Brody disease, characterized by increasing impairment of muscular relaxation during exercise. Alternative splicing results in three transcript variants encoding different isoforms. [provided by RefSeq, Oct 2013]

ATP2A1 Gene-Disease associations (from GenCC):

• Brody myopathy

  Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 16-28904503-C-T is Benign according to our data. Variant chr16-28904503-C-T is described in ClinVar as [Benign]. Clinvar id is 318794.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.138 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABEP2	NM_024816.3	c.*440G>A		3_prime_UTR_variant	Exon 13 of 13	ENST00000358201.9	NP_079092.2
ATP2A1	NM_004320.6	c.*361C>T		downstream_gene_variant		ENST00000395503.9	NP_004311.1
ATP2A1	NM_173201.5	c.*298C>T		downstream_gene_variant			NP_775293.1
ATP2A1	NM_001286075.2	c.*361C>T		downstream_gene_variant			NP_001273004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABEP2	ENST00000358201.9	c.*440G>A		3_prime_UTR_variant	Exon 13 of 13	1	NM_024816.3	ENSP00000350934.4
ATP2A1	ENST00000395503.9	c.*361C>T		downstream_gene_variant		1	NM_004320.6	ENSP00000378879.5

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2442 AN: 152204 Hom.: 68 Cov.: 33

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00943

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.147

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.0169

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00566

Gnomad OTH AF: 0.0134

GnomAD4 exome AF: 0.00803 AC: 10695 AN: 1331860 Hom.: 322 Cov.: 33 AF XY: 0.00790 AC XY: 5182 AN XY: 656234

African (AFR) AF: 0.0214 AC: 650 AN: 30420

American (AMR) AF: 0.00637 AC: 217 AN: 34076

Ashkenazi Jewish (ASJ) AF: 0.00755 AC: 178 AN: 23582

East Asian (EAS) AF: 0.116 AC: 3587 AN: 30868

South Asian (SAS) AF: 0.00261 AC: 203 AN: 77892

European-Finnish (FIN) AF: 0.0188 AC: 550 AN: 29326

Middle Eastern (MID) AF: 0.0143 AC: 74 AN: 5160

European-Non Finnish (NFE) AF: 0.00412 AC: 4305 AN: 1046010

Other (OTH) AF: 0.0171 AC: 931 AN: 54526

GnomAD4 genome AF: 0.0160 AC: 2436 AN: 152322 Hom.: 68 Cov.: 33 AF XY: 0.0167 AC XY: 1240 AN XY: 74470

African (AFR) AF: 0.0220 AC: 913 AN: 41582

American (AMR) AF: 0.00941 AC: 144 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

East Asian (EAS) AF: 0.147 AC: 760 AN: 5174

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4822

European-Finnish (FIN) AF: 0.0169 AC: 179 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00564 AC: 384 AN: 68034

Other (OTH) AF: 0.0137 AC: 29 AN: 2114

Alfa AF: 0.00913 Hom.: 8

Bravo AF: 0.0158

Asia WGS AF: 0.0550 AC: 191 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Brody myopathy Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.4
DANN	Benign	0.70
PhyloP100		-0.11
Mutation Taster		=100/0	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: rs114173613; hg19: chr16-28915824; COSMIC: COSV107431554; COSMIC: COSV107431554;