Variant chr17-40140613-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007359.5(CASC3):c.65G>C(p.Gly22Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000981 in 1,611,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

CASC3
NM_007359.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.086010784).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CASC3	NM_007359.5 linkuse as main transcript	c.65G>C	p.Gly22Ala	missense_variant	1/14	ENST00000264645.12
CASC3	XM_005257163.3 linkuse as main transcript	c.65G>C	p.Gly22Ala	missense_variant	1/14
CASC3	XM_047435623.1 linkuse as main transcript	c.65G>C	p.Gly22Ala	missense_variant	1/9
CASC3	XM_047435624.1 linkuse as main transcript	c.-901G>C		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
CASC3	ENST00000264645.12 linkuse as main transcript	c.65G>C	p.Gly22Ala	missense_variant	1/14	1	NM_007359.5	P1
CASC3	ENST00000418132.7 linkuse as main transcript	n.296G>C		non_coding_transcript_exon_variant	1/8	1
CASC3	ENST00000581849.1 linkuse as main transcript	n.77G>C		non_coding_transcript_exon_variant	1/4	2
CASC3	ENST00000583649.1 linkuse as main transcript	n.70G>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000724

AC:

AN:

152022

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000126

AC:

AN:

237988

Hom.:

AF XY:

0.000145

AC XY:

AN XY:

131132

show subpopulations

Gnomad AFR exome

AF:

0.0000712

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000113

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000209

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000994

AC:

145

AN:

1458872

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

725830

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000110

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152136

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.0000963

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000146

Hom.:

Bravo

AF:

0.000128

ExAC

AF:

0.000100

AC:

Asia WGS

AF:

0.000868

AC:

AN:

3472

EpiCase

AF:

0.000600

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 28, 2022

The c.65G>C (p.G22A) alteration is located in exon 1 (coding exon 1) of the CASC3 gene. This alteration results from a G to C substitution at nucleotide position 65, causing the glycine (G) at amino acid position 22 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

0.12

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.025

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.086

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.28

REVEL

Benign

0.062

Sift

Pathogenic

0.0

Sift4G

Benign

0.12

Polyphen

0.0030

Vest4

0.13

MVP

0.31

MPC

1.9

ClinPred

0.18

GERP RS

3.9

Varity_R

0.38

gMVP

0.33

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over