chr7-94535521-A-G

Variant names:

• chr7-94535521-A-G
• rs779955770
• NM_022900.5:c.841A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022900.5(CASD1):​c.841A>G​(p.Thr281Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,459,176 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CASD1 NM_022900.5 missense, splice_region
• Scores: Splicing: ADA: 0.1184
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.74
• Publications: 0 publications found

Genes affected

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]

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]

SGCE Gene-Disease associations (from GenCC):

• myoclonic dystonia 11

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, Illumina
• myoclonus-dystonia syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000309657 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10394621).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022900.5. 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
	CASD1	NM_022900.5	MANE Select	c.841A>G	p.Thr281Ala	missense splice_region	Exon 8 of 18	NP_075051.4
	CASD1	NM_001363426.1		c.412A>G	p.Thr138Ala	missense splice_region	Exon 9 of 19	NP_001350355.1
	CASD1	NM_001363428.1		c.286A>G	p.Thr96Ala	missense splice_region	Exon 8 of 18	NP_001350357.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASD1	ENST00000297273.9	TSL:1 MANE Select	c.841A>G	p.Thr281Ala	missense splice_region	Exon 8 of 18	ENSP00000297273.4	Q96PB1
	CASD1	ENST00000919855.1		c.841A>G	p.Thr281Ala	missense splice_region	Exon 8 of 18	ENSP00000589914.1
	CASD1	ENST00000919856.1		c.796A>G	p.Thr266Ala	missense splice_region	Exon 7 of 17	ENSP00000589915.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250214 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459176 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726060

African (AFR) AF: 0.00 AC: 0 AN: 33310

American (AMR) AF: 0.0000448 AC: 2 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 86096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110114

Other (OTH) AF: 0.00 AC: 0 AN: 60264

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.020	T
Eigen	Benign	0.019
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0080	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		6.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.73	N
REVEL	Benign	0.060
Sift	Benign	0.50	T
Sift4G	Benign	0.51	T
Polyphen		0.31	B
Vest4		0.34
MutPred		0.23		Gain of helix (P = 0.0696)
MVP		0.26
MPC		0.55
ClinPred		0.40	T
GERP RS		5.2
Varity_R		0.12
gMVP		0.42
Mutation Taster		=76/24	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.12
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.19		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: rs779955770; hg19: chr7-94164833;