7-94597963-C-T

Variant names:

• chr7-94597963-C-T
• rs559235992
• NM_003919.3:c.1253+812G>A

Variant summary

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

The NM_001099401.2(SGCE):​c.1295G>A​(p.Ser432Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0351 in 164,376 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 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. S432C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.036 (160 hom., cov: 31)
  • Exomes 𝑓: 0.028 (9 hom.)
• Consequence: SGCE NM_001099401.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.87
• Publications: 2 publications found

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014960766).
• BP6: Variant 7-94597963-C-T is Benign according to our data. Variant chr7-94597963-C-T is described in ClinVar as Benign. ClinVar VariationId is 235287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.052 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099401.2. 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
	SGCE	NM_003919.3	MANE Select	c.1253+812G>A		intron	N/A	NP_003910.1
	SGCE	NM_001099401.2		c.1295G>A	p.Ser432Asn	missense	Exon 10 of 12	NP_001092871.1
	SGCE	NM_001346713.2		c.1361+812G>A		intron	N/A	NP_001333642.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCE	ENST00000648936.2	MANE Select	c.1253+812G>A		intron	N/A	ENSP00000497130.1
	SGCE	ENST00000428696.7	TSL:1	c.1205+812G>A		intron	N/A	ENSP00000397536.3
	SGCE	ENST00000447873.6	TSL:1	c.1226+812G>A		intron	N/A	ENSP00000388734.1

Frequencies

GnomAD3 genomes AF: 0.0357 AC: 5396 AN: 151088 Hom.: 160 Cov.: 31

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.0349

Gnomad ASJ AF: 0.0208

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0105

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0535

Gnomad OTH AF: 0.0313

GnomAD2 exomes AF: 0.0171 AC: 60 AN: 3508 AF XY: 0.0186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.00505

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0144

Gnomad NFE exome AF: 0.0239

Gnomad OTH exome AF: 0.0106

GnomAD4 exome AF: 0.0279 AC: 367 AN: 13174 Hom.: 9 Cov.: 0 AF XY: 0.0299 AC XY: 274 AN XY: 9174

African (AFR) AF: 0.00 AC: 0 AN: 202

American (AMR) AF: 0.0228 AC: 15 AN: 658

Ashkenazi Jewish (ASJ) AF: 0.00311 AC: 1 AN: 322

East Asian (EAS) AF: 0.00 AC: 0 AN: 410

South Asian (SAS) AF: 0.00401 AC: 5 AN: 1246

European-Finnish (FIN) AF: 0.0161 AC: 10 AN: 622

Middle Eastern (MID) AF: 0.0185 AC: 3 AN: 162

European-Non Finnish (NFE) AF: 0.0357 AC: 321 AN: 8992

Other (OTH) AF: 0.0214 AC: 12 AN: 560

GnomAD4 genome AF: 0.0357 AC: 5396 AN: 151202 Hom.: 160 Cov.: 31 AF XY: 0.0335 AC XY: 2475 AN XY: 73820

African (AFR) AF: 0.0107 AC: 440 AN: 41162

American (AMR) AF: 0.0348 AC: 529 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.0208 AC: 72 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.0107 AC: 51 AN: 4766

European-Finnish (FIN) AF: 0.0309 AC: 320 AN: 10366

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0535 AC: 3627 AN: 67824

Other (OTH) AF: 0.0310 AC: 65 AN: 2100

Alfa AF: 0.0195 Hom.: 9

Bravo AF: 0.0358

ExAC AF: 0.00446 AC: 46

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.9
DANN	Benign	0.15
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.00017	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
PhyloP100		-1.9
PROVEAN	Benign	0.30	N
REVEL	Benign	0.012
Sift	Benign	0.75	T
Sift4G	Benign	1.0	T
Vest4		0.037
MPC		0.18
ClinPred		0.0073	T
GERP RS		-0.23
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs559235992; hg19: chr7-94227275; COSMIC: COSV108107853; COSMIC: COSV108107853;