chr20-56437529-C-T

Variant names:

• chr20-56437529-C-T
• rs201516954
• NM_020356.4:c.402C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_020356.4(CASS4):​c.402C>T​(p.Pro134Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,578,720 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: CASS4 NM_020356.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.895
• Publications: 2 publications found

Genes affected

CASS4 (HGNC:15878): (Cas scaffold protein family member 4) Enables protein tyrosine kinase binding activity. Involved in several processes, including positive regulation of protein kinase B signaling; positive regulation of protein tyrosine kinase activity; and positive regulation of substrate adhesion-dependent cell spreading. Located in focal adhesion. Part of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 20-56437529-C-T is Benign according to our data. Variant chr20-56437529-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3485355.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.895 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASS4	NM_020356.4	c.402C>T	p.Pro134Pro	synonymous_variant	Exon 2 of 6	ENST00000679887.1	NP_065089.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASS4	ENST00000679887.1	c.402C>T	p.Pro134Pro	synonymous_variant	Exon 2 of 6		NM_020356.4	ENSP00000506506.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000365 AC: 8 AN: 219266 AF XY: 0.0000418

Gnomad AFR exome AF: 0.0000666

Gnomad AMR exome AF: 0.000107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000993

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000372 AC: 53 AN: 1426384 Hom.: 0 Cov.: 32 AF XY: 0.0000396 AC XY: 28 AN XY: 706768

African (AFR) AF: 0.0000312 AC: 1 AN: 32050

American (AMR) AF: 0.000105 AC: 4 AN: 38004

Ashkenazi Jewish (ASJ) AF: 0.0000422 AC: 1 AN: 23722

East Asian (EAS) AF: 0.000738 AC: 29 AN: 39286

South Asian (SAS) AF: 0.0000365 AC: 3 AN: 82222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5546

European-Non Finnish (NFE) AF: 0.0000137 AC: 15 AN: 1094938

Other (OTH) AF: 0.00 AC: 0 AN: 58676

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152336 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74496

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000330 Hom.: 0

Bravo AF: 0.00000756

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 06, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.3
DANN	Benign	0.58
PhyloP100		-0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs201516954; hg19: chr20-55012585; COSMIC: COSV64387884;