rs557861177

Variant names:

• chr7-94623379-G-A
• rs557861177
• NM_003919.3:c.409C>T
• SGCE p.Arg137Cys

Your query was ambiguous. Multiple possible variants found:

• chr7-94623379-G-A
• chr7-94623379-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_003919.3(SGCE):​c.409C>T​(p.Arg137Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000499 in 1,602,254 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R137H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: SGCE NM_003919.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.54
• Publications: 0 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000657 (10/152106) while in subpopulation AMR AF = 0.000458 (7/15270). AF 95% confidence interval is 0.000215. There are 0 homozygotes in GnomAd4. There are 7 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 10 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.409C>T	p.Arg137Cys	missense	Exon 4 of 11	NP_003910.1	A0A0S2Z4P5
	SGCE	NM_001346713.2		c.517C>T	p.Arg173Cys	missense	Exon 5 of 12	NP_001333642.1	A0A2R8YGQ3
	SGCE	NM_001346715.2		c.517C>T	p.Arg173Cys	missense	Exon 5 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.409C>T	p.Arg137Cys	missense	Exon 4 of 11	ENSP00000497130.1	O43556-1
	SGCE	ENST00000428696.7	TSL:1	c.409C>T	p.Arg137Cys	missense	Exon 4 of 11	ENSP00000397536.3	A0A2U3TZN7
	SGCE	ENST00000447873.6	TSL:1	c.409C>T	p.Arg137Cys	missense	Exon 4 of 10	ENSP00000388734.1	C9JR67

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 151988 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

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: 0.00

GnomAD2 exomes AF: 0.0000602 AC: 15 AN: 249078 AF XY: 0.0000445

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000355

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000483 AC: 70 AN: 1450148 Hom.: 0 Cov.: 26 AF XY: 0.0000374 AC XY: 27 AN XY: 721982

African (AFR) AF: 0.0000302 AC: 1 AN: 33166

American (AMR) AF: 0.000337 AC: 15 AN: 44542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26002

East Asian (EAS) AF: 0.0000507 AC: 2 AN: 39468

South Asian (SAS) AF: 0.00 AC: 0 AN: 85442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5692

European-Non Finnish (NFE) AF: 0.0000472 AC: 52 AN: 1102630

Other (OTH) AF: 0.00 AC: 0 AN: 59932

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152106 Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7 AN XY: 74368

African (AFR) AF: 0.0000482 AC: 2 AN: 41508

American (AMR) AF: 0.000458 AC: 7 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000901 Hom.: 0

Bravo AF: 0.0000945

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Myoclonic dystonia 11 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.83
Sift	Benign	0.031	D
Sift4G	Uncertain	0.0090	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.30
gMVP		0.77
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs557861177;

hg19: chr7-94252691;

COSMIC: COSV56017024;

COSMIC: COSV56017024;