7-94537790-A-G

Variant summary

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

The NM_022900.5(CASD1):c.1162A>G(p.Asn388Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,613,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CASD1 NM_022900.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33

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=0.035090625).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASD1	NM_022900.5	c.1162A>G	p.Asn388Asp	missense_variant	9/18	ENST00000297273.9
LOC105375404	XR_007060433.1	n.75-5812T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASD1	ENST00000297273.9	c.1162A>G	p.Asn388Asp	missense_variant	9/18	1	NM_022900.5	P1
SGCE	ENST00000645624.1	n.834-13517T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152106 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD3 exomes AF: 0.0000638 AC: 16 AN: 250612 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135510

Gnomad AFR exome AF: 0.000681

Gnomad AMR exome AF: 0.000145

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: 0.0000199 AC: 29 AN: 1460800 Hom.: 0 Cov.: 30 AF XY: 0.0000206 AC XY: 15 AN XY: 726750

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.0000895

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000663

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152224 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74416

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000411 Hom.: 0

Bravo AF: 0.000200

ESP6500AA AF: 0.000909 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000741 AC: 9

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

Jul 14, 2021

The c.1162A>G (p.N388D) alteration is located in exon 9 (coding exon 9) of the CASD1 gene. This alteration results from a A to G substitution at nucleotide position 1162, causing the asparagine (N) at amino acid position 388 to be replaced by an aspartic acid (D). 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	0.064
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.075	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.092
Sift	Benign	0.17	T
Sift4G	Benign	0.37	T
Polyphen		0.0010	B
Vest4		0.19
MVP		0.32
MPC		0.45
ClinPred		0.026	T
GERP RS		2.9
Varity_R		0.21
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs116301340; hg19: chr7-94167102;