chr17-40140772-C-G

Variant names:

• chr17-40140772-C-G
• NM_007359.5:c.224C>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_007359.5(CASC3):​c.224C>G​(p.Ser75Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000584 in 1,027,596 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: CASC3 NM_007359.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.96

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC3	NM_007359.5	c.224C>G	p.Ser75Trp	missense_variant	Exon 1 of 14	ENST00000264645.12	NP_031385.2
CASC3	XM_005257163.3	c.224C>G	p.Ser75Trp	missense_variant	Exon 1 of 14		XP_005257220.1
CASC3	XM_047435623.1	c.224C>G	p.Ser75Trp	missense_variant	Exon 1 of 9		XP_047291579.1
CASC3	XM_047435624.1	c.-742C>G		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	c.224C>G	p.Ser75Trp	missense_variant	Exon 1 of 14	1	NM_007359.5	ENSP00000264645.6

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000584 AC: 6 AN: 1027596 Hom.: 0 Cov.: 33 AF XY: 0.00000810 AC XY: 4 AN XY: 493848

Gnomad4 AFR exome AF: 0.0000475

Gnomad4 AMR exome AF: 0.00

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: 0.00000586

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 21

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.74	D
LIST_S2	Uncertain	0.89	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.16
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.19		Loss of phosphorylation at S75 (P = 0.0017);
MVP		0.42
MPC		2.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.63
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38297025;