7-94603346-T-G

Variant names:

• chr7-94603346-T-G
• rs116105264
• NM_003919.3:c.769A>C

Variant summary

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

The NM_003919.3(SGCE):​c.769A>C​(p.Thr257Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000519 in 1,612,732 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T257I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (2 hom.)
• Consequence: SGCE NM_003919.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.67
• Publications: 5 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=0.018404633).
• BP6: Variant 7-94603346-T-G is Benign according to our data. Variant chr7-94603346-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00269 (410/152290) while in subpopulation AFR AF = 0.00948 (394/41562). AF 95% confidence interval is 0.00871. There are 0 homozygotes in GnomAd4. There are 193 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 410 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003919.3. 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.769A>C	p.Thr257Pro	missense	Exon 6 of 11	NP_003910.1	A0A0S2Z4P5
	SGCE	NM_001346713.2		c.877A>C	p.Thr293Pro	missense	Exon 7 of 12	NP_001333642.1	A0A2R8YGQ3
	SGCE	NM_001346715.2		c.877A>C	p.Thr293Pro	missense	Exon 7 of 11	NP_001333644.1	A0A2R8Y5J3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGCE	ENST00000648936.2	MANE Select	c.769A>C	p.Thr257Pro	missense	Exon 6 of 11	ENSP00000497130.1	O43556-1
	SGCE	ENST00000428696.7	TSL:1	c.748A>C	p.Thr250Pro	missense	Exon 6 of 11	ENSP00000397536.3	A0A2U3TZN7
	SGCE	ENST00000447873.6	TSL:1	c.769A>C	p.Thr257Pro	missense	Exon 6 of 10	ENSP00000388734.1	C9JR67

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 409 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00948

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000709 AC: 177 AN: 249796 AF XY: 0.000600

Gnomad AFR exome AF: 0.00994

Gnomad AMR exome AF: 0.000349

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000292 AC: 427 AN: 1460442 Hom.: 2 Cov.: 30 AF XY: 0.000271 AC XY: 197 AN XY: 726548

African (AFR) AF: 0.0105 AC: 352 AN: 33440

American (AMR) AF: 0.000470 AC: 21 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111010

Other (OTH) AF: 0.000713 AC: 43 AN: 60330

GnomAD4 genome AF: 0.00269 AC: 410 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00259 AC XY: 193 AN XY: 74462

African (AFR) AF: 0.00948 AC: 394 AN: 41562

American (AMR) AF: 0.000785 AC: 12 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68014

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000865 Hom.: 1

Bravo AF: 0.00287

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000832 AC: 101

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Myoclonic dystonia 11 (2)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.76	N
PhyloP100		7.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.83	N
REVEL	Pathogenic	0.66
Sift	Benign	0.28	T
Sift4G	Benign	0.21	T
Polyphen		0.89	P
Vest4		0.52
MVP		0.86
MPC		0.76
ClinPred		0.026	T
GERP RS		5.0
PromoterAI		0.026	Neutral
Varity_R		0.34
gMVP		0.79
Mutation Taster		=40/60	disease causing

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: rs116105264; hg19: chr7-94232658;