chr17-40140569-G-C

Variant names:

• chr17-40140569-G-C
• NM_007359.5:c.21G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007359.5(CASC3):​c.21G>C​(p.Gln7His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: CASC3 NM_007359.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34959286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASC3	NM_007359.5	c.21G>C	p.Gln7His	missense_variant	Exon 1 of 14	ENST00000264645.12	NP_031385.2
CASC3	XM_005257163.3	c.21G>C	p.Gln7His	missense_variant	Exon 1 of 14		XP_005257220.1
CASC3	XM_047435623.1	c.21G>C	p.Gln7His	missense_variant	Exon 1 of 9		XP_047291579.1
CASC3	XM_047435624.1	c.-945G>C		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.21G>C	p.Gln7His	missense_variant	Exon 1 of 14	1	NM_007359.5	ENSP00000264645.6
CASC3	ENST00000418132.7	n.252G>C		non_coding_transcript_exon_variant	Exon 1 of 8	1
CASC3	ENST00000581849.1	n.33G>C		non_coding_transcript_exon_variant	Exon 1 of 4	2
CASC3	ENST00000583649.1	n.26G>C		non_coding_transcript_exon_variant	Exon 1 of 2	3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.21G>C (p.Q7H) 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 21, causing the glutamine (Q) at amino acid position 7 to be replaced by a histidine (H). 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	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.028	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.39	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.55	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.48	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Polyphen		0.99	D
Vest4		0.47
MutPred		0.13		Loss of helix (P = 0.028);
MVP		0.43
MPC		1.7
ClinPred		0.87	D
GERP RS		3.9
Varity_R		0.30
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-38296822;