7-94551390-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022900.5(CASD1):c.1868G>A(p.Arg623His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000333 in 1,557,156 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (0 hom.)
• Consequence: CASD1 NM_022900.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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]

LOC105375404 (HGNC:):

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.023097754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASD1	NM_022900.5	c.1868G>A	p.Arg623His	missense_variant	15/18	ENST00000297273.9
LOC105375404	XR_007060433.1	n.74+7032C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASD1	ENST00000297273.9	c.1868G>A	p.Arg623His	missense_variant	15/18	1	NM_022900.5	P1
SGCE	ENST00000645624.1	n.834-27117C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 151958 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000235

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.000117 AC: 24 AN: 205014 Hom.: 0 AF XY: 0.000116 AC XY: 13 AN XY: 112484

Gnomad AFR exome AF: 0.0000770

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000745

Gnomad SAS exome AF: 0.000171

Gnomad FIN exome AF: 0.0000480

Gnomad NFE exome AF: 0.000173

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000349 AC: 490 AN: 1405080 Hom.: 0 Cov.: 28 AF XY: 0.000348 AC XY: 243 AN XY: 698052

Gnomad4 AFR exome AF: 0.000136

Gnomad4 AMR exome AF: 0.0000310

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000277

Gnomad4 SAS exome AF: 0.000226

Gnomad4 FIN exome AF: 0.0000569

Gnomad4 NFE exome AF: 0.000415

Gnomad4 OTH exome AF: 0.000189

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152076 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74360

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.000475

Alfa AF: 0.000205 Hom.: 0

Bravo AF: 0.000181

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000107 AC: 13

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 16, 2023

The c.1868G>A (p.R623H) alteration is located in exon 15 (coding exon 15) of the CASD1 gene. This alteration results from a G to A substitution at nucleotide position 1868, causing the arginine (R) at amino acid position 623 to be replaced by a histidine (H). 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	0.078
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.59
Cadd	Benign	22
Dann	Benign	0.95
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.17	N
MutationTaster	Benign	0.73	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.7	N
REVEL	Benign	0.055
Sift	Benign	0.29	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.18
MPC		0.48
ClinPred		0.050	T
GERP RS		2.8
Varity_R		0.031
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs150476678; hg19: chr7-94180702;