chr17-40140770-G-A

Variant names:

• chr17-40140770-G-A
• rs1349888954
• NM_007359.5:c.222G>A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_007359.5(CASC3):​c.222G>A​(p.Glu74Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000149 in 1,338,696 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: not found (cov: 27)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: CASC3 NM_007359.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.41

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP7: Synonymous conserved (PhyloP=3.41 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC3	NM_007359.5	c.222G>A	p.Glu74Glu	synonymous_variant	Exon 1 of 14	ENST00000264645.12	NP_031385.2
CASC3	XM_005257163.3	c.222G>A	p.Glu74Glu	synonymous_variant	Exon 1 of 14		XP_005257220.1
CASC3	XM_047435623.1	c.222G>A	p.Glu74Glu	synonymous_variant	Exon 1 of 9		XP_047291579.1
CASC3	XM_047435624.1	c.-744G>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	c.222G>A	p.Glu74Glu	synonymous_variant	Exon 1 of 14	1	NM_007359.5	ENSP00000264645.6

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000149 AC: 2 AN: 1338696 Hom.: 0 Cov.: 33 AF XY: 0.00000153 AC XY: 1 AN XY: 655566

Gnomad4 AFR exome AF: 0.00

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: 0.00000190

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs1349888954; hg19: chr17-38297023;