Genetic Variant CAST:p.Ser306Ser (chr5-96740783-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001750.7(CAST):c.918G>T(p.Ser306Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars). Synonymous variant affecting the same amino acid position (i.e. S306S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CAST
NM_001750.7 splice_region, synonymous

Scores

Splicing: ADA: 0.9993

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.08

Publications

0 publications found

Variant links:

Genes affected

CAST (HGNC:1515): (calpastatin) The protein encoded by this gene is an endogenous calpain (calcium-dependent cysteine protease) inhibitor. It consists of an N-terminal domain L and four repetitive calpain-inhibition domains (domains 1-4), and it is involved in the proteolysis of amyloid precursor protein. The calpain/calpastatin system is involved in numerous membrane fusion events, such as neural vesicle exocytosis and platelet and red-cell aggregation. The encoded protein is also thought to affect the expression levels of genes encoding structural or regulatory proteins. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2010]

CAST Gene-Disease associations (from GenCC):

peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

CAST links:

CAST (HGNC:):

CAST links:

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new If you want to explore the variant's impact on the transcript NM_001750.7, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001750.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CAST	NM_001750.7	MANE Select	c.918G>T	p.Ser306Ser	splice_region synonymous	Exon 13 of 32	NP_001741.4
CAST	NM_001042441.3		c.861G>T	p.Ser287Ser	splice_region synonymous	Exon 12 of 31	NP_001035906.1	P20810-7
CAST	NM_001042442.3		c.852G>T	p.Ser284Ser	splice_region synonymous	Exon 12 of 31	NP_001035907.1	P20810-10

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CAST	ENST00000675179.1	MANE Select	c.918G>T	p.Ser306Ser	splice_region synonymous	Exon 13 of 32	ENSP00000501872.1
CAST	ENST00000341926.7	TSL:1	c.669G>T	p.Ser223Ser	splice_region synonymous	Exon 11 of 30	ENSP00000339914.3
CAST	ENST00000309190.9	TSL:1	c.603G>T	p.Ser201Ser	splice_region synonymous	Exon 10 of 29	ENSP00000312523.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1430152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713330

African (AFR)

AF:

0.00

AC:

AN:

33014

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25932

East Asian (EAS)

AF:

0.00

AC:

AN:

39568

South Asian (SAS)

AF:

0.00

AC:

AN:

85604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1083016

Other (OTH)

AF:

0.00

AC:

AN:

59300

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.73

PhyloP100

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

3.0

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.85

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.27

Position offset: 0

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over