7-94535521-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_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. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

Variant links:

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]

CASD1 links:

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 links:

LOC105375404 (HGNC:):

LOC105375404 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10394621).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASD1	NM_022900.5 link	c.841A>G	p.Thr281Ala	missense_variant, splice_region_variant	Exon 8 of 18	ENST00000297273.9	NP_075051.4	Q96PB1Q8WZ77

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CASD1	ENST00000297273.9 link	c.841A>G	p.Thr281Ala	missense_variant, splice_region_variant	Exon 8 of 18	1	NM_022900.5	ENSP00000297273.4	Q96PB1
CASD1	ENST00000443644.1 link	n.*485A>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 6	5		ENSP00000389718.1	F8WDQ7
CASD1	ENST00000443644.1 link	n.*485A>G		3_prime_UTR_variant	Exon 6 of 6	5		ENSP00000389718.1	F8WDQ7
SGCE	ENST00000645624.1 link	n.834-11248T>C		intron_variant	Intron 6 of 6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000799

AC:

AN:

250214

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135242

show subpopulations

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 SAS 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:

AN:

1459176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.841A>G (p.T281A) alteration is located in exon 8 (coding exon 8) of the CASD1 gene. This alteration results from a A to G substitution at nucleotide position 841, causing the threonine (T) at amino acid position 281 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.020

Eigen

Benign

0.019

Eigen_PC

Benign

0.19

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0080

MetaRNN

Benign

0.10

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-0.73

REVEL

Benign

0.060

Sift

Benign

0.50

Sift4G

Benign

0.51

Polyphen

0.31

Vest4

0.34

MutPred

0.23

Gain of helix (P = 0.0696);

MVP

0.26

MPC

0.55

ClinPred

0.40

GERP RS

5.2

Varity_R

0.12

gMVP

0.42

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over