Genetic Variant CASS4:p.Leu71Leu (chr20-56437340-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_020356.4(CASS4):c.213C>T(p.Leu71Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00241 in 1,614,066 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 34 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 33 hom. )

Consequence

CASS4
NM_020356.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.973

Variant links:

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]

CASS4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 20-56437340-C-T is Benign according to our data. Variant chr20-56437340-C-T is described in ClinVar as [Benign]. Clinvar id is 778896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.973 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0112 (1713/152350) while in subpopulation AFR AF = 0.0373 (1551/41576). AF 95% confidence interval is 0.0358. There are 34 homozygotes in GnomAd4. There are 813 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 34 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASS4	NM_020356.4 link	c.213C>T	p.Leu71Leu	synonymous_variant	Exon 2 of 6	ENST00000679887.1	NP_065089.2	Q9NQ75-1B4DII4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASS4	ENST00000679887.1 link	c.213C>T	p.Leu71Leu	synonymous_variant	Exon 2 of 6		NM_020356.4	ENSP00000506506.1		Q9NQ75-1

Frequencies

GnomAD3 genomes

AF:

0.0113

AC:

1713

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0374

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00562

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000485

Gnomad OTH

AF:

0.0181

GnomAD2 exomes

AF:

0.00358

AC:

896

AN:

250574

AF XY:

0.00249

show subpopulations

Gnomad AFR exome

AF:

0.0398

Gnomad AMR exome

AF:

0.00464

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000583

Gnomad OTH exome

AF:

0.00344

GnomAD4 exome

AF:

0.00149

AC:

2172

AN:

1461716

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

960

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.0387

AC:

1296

AN:

33478

American (AMR)

AF:

0.00474

AC:

212

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000268

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86220

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000337

AC:

375

AN:

1111944

Other (OTH)

AF:

0.00396

AC:

239

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

126

252

378

504

630

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0112

AC:

1713

AN:

152350

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

813

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0373

AC:

1551

AN:

41576

American (AMR)

AF:

0.00562

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000207

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000485

AC:

AN:

68032

Other (OTH)

AF:

0.0180

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

161

241

322

402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00630

Hom.:

Bravo

AF:

0.0129

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000949

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.70

CADD

Benign

7.1

(source)

DANN

Benign

0.71

PhyloP100

-0.97

Mutation Taster

=100/0

polymorphism

(source)

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

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20-56437340-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over