dbSNP rs184119888: CASC3:p.Gly22Asp (chr17-40140613-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_007359.5(CASC3):c.65G>A(p.Gly22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000891 in 1,611,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00090 ( 0 hom. )

Consequence

CASC3
NM_007359.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.31

Variant links:

Genes affected

CASC3 (HGNC:17040): (CASC3 exon junction complex subunit) The product of this gene is a core component of the exon junction complex (EJC), a protein complex that is deposited on spliced mRNAs at exon-exon junctions and functions in nonsense-mediated mRNA decay (NMD). The encoded protein binds RNA and interacts with two other EJC core components. It is predominantly located in the cytoplasm, but shuttles into the nucleus where it localizes to nuclear speckles. [provided by RefSeq, Jul 2008]

CASC3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.053804576).

BS2

High AC in GnomAd4 at 124 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC3	NM_007359.5 link	c.65G>A	p.Gly22Asp	missense_variant	Exon 1 of 14	ENST00000264645.12	NP_031385.2
CASC3	XM_005257163.3 link	c.65G>A	p.Gly22Asp	missense_variant	Exon 1 of 14		XP_005257220.1	O15234
CASC3	XM_047435623.1 link	c.65G>A	p.Gly22Asp	missense_variant	Exon 1 of 9		XP_047291579.1
CASC3	XM_047435624.1 link	c.-901G>A		5_prime_UTR_variant	Exon 1 of 15		XP_047291580.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASC3	ENST00000264645.12 link	c.65G>A	p.Gly22Asp	missense_variant	Exon 1 of 14	1	NM_007359.5	ENSP00000264645.6		O15234

Frequencies

GnomAD3 genomes

AF:

0.000816

AC:

124

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000870

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00110

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000454

AC:

108

AN:

237988

Hom.:

AF XY:

0.000412

AC XY:

AN XY:

131132

show subpopulations

Gnomad AFR exome

AF:

0.000925

Gnomad AMR exome

AF:

0.000671

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000566

Gnomad SAS exome

AF:

0.0000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000627

Gnomad OTH exome

AF:

0.000681

GnomAD4 exome

AF:

0.000899

AC:

1311

AN:

1458872

Hom.:

Cov.:

AF XY:

0.000891

AC XY:

647

AN XY:

725830

show subpopulations

Gnomad4 AFR exome

AF:

0.000961

Gnomad4 AMR exome

AF:

0.000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000194

Gnomad4 NFE exome

AF:

0.00108

Gnomad4 OTH exome

AF:

0.000630

GnomAD4 genome

AF:

0.000815

AC:

124

AN:

152136

Hom.:

Cov.:

AF XY:

0.000820

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000867

Gnomad4 AMR

AF:

0.000719

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00110

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.000788

Hom.:

Bravo

AF:

0.000824

ESP6500AA

AF:

0.000470

AC:

ESP6500EA

AF:

0.000714

AC:

ExAC

AF:

0.000358

AC:

EpiCase

AF:

0.00104

EpiControl

AF:

0.000712

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

Eigen

Benign

0.082

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.53

LIST_S2

Benign

0.75

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.97

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.96

REVEL

Benign

0.14

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0060

Polyphen

0.87

Vest4

0.39

MVP

0.28

MPC

2.1

ClinPred

0.091

GERP RS

3.9

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.2

Varity_R

0.61

gMVP

0.35

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over