7-94597964-T-G

Position:

• chr7-94597964-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001099401.2(SGCE):​c.1294A>C​(p.Ser432Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.775 in 163,502 control chromosomes in the GnomAD database, including 49,920 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/15 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S432N) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.78 (46964 hom., cov: 26)
  • Exomes 𝑓: 0.68 (2956 hom.)
• Consequence: SGCE NM_001099401.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0440

Genes affected

SGCE (HGNC:10808): (sarcoglycan epsilon) This gene encodes the epsilon member of the sarcoglycan family. Sarcoglycans are transmembrane proteins that are components of the dystrophin-glycoprotein complex, which link the actin cytoskeleton to the extracellular matrix. Unlike other family members which are predominantly expressed in striated muscle, the epsilon sarcoglycan is more broadly expressed. Mutations in this gene are associated with myoclonus-dystonia syndrome. This gene is imprinted, with preferential expression from the paternal allele. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. A pseudogene associated with this gene is located on chromosome 2. [provided by RefSeq, Oct 2016]

CASD1 (HGNC:16014): (CAS1 domain containing 1) Enables N-acetylneuraminate 7-O(or 9-O)-acetyltransferase activity. Involved in carbohydrate metabolic process. Is integral component of Golgi membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.6818324E-6).
• BP6: Variant 7-94597964-T-G is Benign according to our data. Variant chr7-94597964-T-G is described in ClinVar as [Benign]. Clinvar id is 487363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-94597964-T-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGCE	NM_003919.3	c.1253+811A>C		intron_variant		ENST00000648936.2	NP_003910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGCE	ENST00000648936.2	c.1253+811A>C		intron_variant			NM_003919.3	ENSP00000497130.1

Frequencies

GnomAD3 genomes AF: 0.782 AC: 118193 AN: 151164 Hom.: 46913 Cov.: 26

Gnomad AFR AF: 0.922

Gnomad AMI AF: 0.858

Gnomad AMR AF: 0.728

Gnomad ASJ AF: 0.762

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.646

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.729

Gnomad NFE AF: 0.718

Gnomad OTH AF: 0.750

GnomAD3 exomes AF: 0.666 AC: 2237 AN: 3360 Hom.: 748 AF XY: 0.673 AC XY: 1367 AN XY: 2030

Gnomad AFR exome AF: 0.964

Gnomad AMR exome AF: 0.491

Gnomad ASJ exome AF: 0.705

Gnomad EAS exome AF: 0.694

Gnomad SAS exome AF: 0.559

Gnomad FIN exome AF: 0.778

Gnomad NFE exome AF: 0.689

Gnomad OTH exome AF: 0.739

GnomAD4 exome AF: 0.682 AC: 8335 AN: 12222 Hom.: 2956 Cov.: 0 AF XY: 0.687 AC XY: 5887 AN XY: 8564

Gnomad4 AFR exome AF: 0.892

Gnomad4 AMR exome AF: 0.527

Gnomad4 ASJ exome AF: 0.687

Gnomad4 EAS exome AF: 0.780

Gnomad4 SAS exome AF: 0.527

Gnomad4 FIN exome AF: 0.766

Gnomad4 NFE exome AF: 0.698

Gnomad4 OTH exome AF: 0.658

GnomAD4 genome AF: 0.782 AC: 118302 AN: 151280 Hom.: 46964 Cov.: 26 AF XY: 0.784 AC XY: 57865 AN XY: 73842

Gnomad4 AFR AF: 0.922

Gnomad4 AMR AF: 0.728

Gnomad4 ASJ AF: 0.762

Gnomad4 EAS AF: 0.748

Gnomad4 SAS AF: 0.645

Gnomad4 FIN AF: 0.811

Gnomad4 NFE AF: 0.718

Gnomad4 OTH AF: 0.751

Alfa AF: 0.667 Hom.: 1934

Bravo AF: 0.784

TwinsUK AF: 0.712 AC: 2639

ALSPAC AF: 0.716 AC: 2759

ExAC AF: 0.524 AC: 4307

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myoclonic dystonia 11 Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 13, 2017	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.5
DANN	Benign	0.052
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.000060	N
LIST_S2	Benign	0.28	T;T;T;T;T
MetaRNN	Benign	0.0000017	T;T;T;T;T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	0.24	N;.;.;.;.
REVEL	Benign	0.018
Sift	Benign	0.49	T;.;.;.;.
Sift4G	Benign	0.43	T;.;.;.;.
Vest4		0.012
MutPred		0.32		Loss of glycosylation at S432 (P = 0.0514);Loss of glycosylation at S432 (P = 0.0514);.;.;.;
MPC		0.22
ClinPred		0.00014	T
GERP RS		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs10247562; hg19: chr7-94227276;