dbSNP rs766998291: CASC3:p.Glu74Gly (chr17-40140769-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_007359.5(CASC3):c.221A>G(p.Glu74Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000667 in 1,169,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E74D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000050 ( 0 hom., cov: 24)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

CASC3
NM_007359.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.79

Publications

1 publications found

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:

ENSG00000310351 (HGNC:):

ENSG00000310351 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.21066335).

BS2

High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007359.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASC3	NM_007359.5	MANE Select	c.221A>G	p.Glu74Gly	missense	Exon 1 of 14	NP_031385.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASC3	ENST00000264645.12	TSL:1 MANE Select	c.221A>G	p.Glu74Gly	missense	Exon 1 of 14	ENSP00000264645.6	O15234
CASC3	ENST00000418132.7	TSL:1	n.452A>G		non_coding_transcript_exon	Exon 1 of 8
CASC3	ENST00000971362.1		c.221A>G	p.Glu74Gly	missense	Exon 1 of 14	ENSP00000641421.1

Frequencies

GnomAD3 genomes

AF:

0.0000503

AC:

AN:

99416

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000784

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:

0.0000576

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000126

AC:

AN:

79392

AF XY:

0.000118

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000221

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000143

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000190

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000682

AC:

AN:

1070112

Hom.:

Cov.:

AF XY:

0.0000502

AC XY:

AN XY:

517730

show subpopulations

African (AFR)

AF:

0.0000460

AC:

AN:

21722

American (AMR)

AF:

0.000262

AC:

AN:

19052

Ashkenazi Jewish (ASJ)

AF:

0.0000870

AC:

AN:

11498

East Asian (EAS)

AF:

0.0000882

AC:

AN:

11334

South Asian (SAS)

AF:

0.0000777

AC:

AN:

64314

European-Finnish (FIN)

AF:

0.0000434

AC:

AN:

23066

Middle Eastern (MID)

AF:

0.000412

AC:

AN:

2426

European-Non Finnish (NFE)

AF:

0.0000626

AC:

AN:

879048

Other (OTH)

AF:

0.0000797

AC:

AN:

37652

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000503

AC:

AN:

99416

Hom.:

Cov.:

AF XY:

0.0000437

AC XY:

AN XY:

45770

show subpopulations

African (AFR)

AF:

0.0000784

AC:

AN:

25502

American (AMR)

AF:

0.00

AC:

AN:

7288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2830

East Asian (EAS)

AF:

0.00

AC:

AN:

3190

South Asian (SAS)

AF:

0.00

AC:

AN:

2698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3534

Middle Eastern (MID)

AF:

0.00

AC:

AN:

222

European-Non Finnish (NFE)

AF:

0.0000576

AC:

AN:

52100

Other (OTH)

AF:

0.00

AC:

AN:

1312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000437

Hom.:

ExAC

AF:

0.0000325

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.21

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.065

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.74

M_CAP

Pathogenic

0.51

MetaRNN

Benign

0.21

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.0

PhyloP100

5.8

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.8

REVEL

Benign

0.094

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0060

Polyphen

0.73

Vest4

0.39

MVP

0.21

MPC

1.9

ClinPred

0.23

GERP RS

4.9

PromoterAI

-0.063

Neutral

(source)

Varity_R

0.30

gMVP

0.14

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over