Genetic Variant CASS4:c.643-96T>C (chr20-56451723-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_020356.4(CASS4):c.643-96T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0524 in 886,538 control chromosomes in the GnomAD database, including 1,297 homozygotes. 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: 𝑓 0.055 ( 259 hom., cov: 32)

Exomes 𝑓: 0.052 ( 1038 hom. )

Consequence

CASS4
NM_020356.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.819

Publications

7 publications found

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0742 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020356.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CASS4	NM_020356.4	MANE Select	c.643-96T>C	intron	N/A	NP_065089.2	Q9NQ75-1
CASS4	NM_001164116.2		c.643-96T>C	intron	N/A	NP_001157588.1	Q9NQ75-1
CASS4	NM_001164114.2		c.481-96T>C	intron	N/A	NP_001157586.1	B4DII4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CASS4	ENST00000679887.1	MANE Select	c.643-96T>C	intron	N/A	ENSP00000506506.1	Q9NQ75-1
CASS4	ENST00000360314.7	TSL:1	c.643-96T>C	intron	N/A	ENSP00000353462.3	Q9NQ75-1
CASS4	ENST00000497244.1	TSL:1	n.794-96T>C	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0554

AC:

8426

AN:

152118

Hom.:

261

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0763

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0393

Gnomad ASJ

AF:

0.0415

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0555

Gnomad FIN

AF:

0.0355

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0545

Gnomad OTH

AF:

0.0555

GnomAD4 exome

AF:

0.0518

AC:

38010

AN:

734302

Hom.:

1038

AF XY:

0.0522

AC XY:

19813

AN XY:

379260

show subpopulations

African (AFR)

AF:

0.0757

AC:

1368

AN:

18072

American (AMR)

AF:

0.0308

AC:

811

AN:

26326

Ashkenazi Jewish (ASJ)

AF:

0.0432

AC:

692

AN:

16018

East Asian (EAS)

AF:

0.000309

AC:

AN:

35566

South Asian (SAS)

AF:

0.0590

AC:

3244

AN:

54972

European-Finnish (FIN)

AF:

0.0381

AC:

1811

AN:

47490

Middle Eastern (MID)

AF:

0.0639

AC:

163

AN:

2552

European-Non Finnish (NFE)

AF:

0.0561

AC:

27930

AN:

497866

Other (OTH)

AF:

0.0559

AC:

1980

AN:

35440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1853

3707

5560

7414

9267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

698

1396

2094

2792

3490

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0554

AC:

8431

AN:

152236

Hom.:

259

Cov.:

AF XY:

0.0544

AC XY:

4048

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0765

AC:

3175

AN:

41524

American (AMR)

AF:

0.0392

AC:

600

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0415

AC:

144

AN:

3466

East Asian (EAS)

AF:

0.000386

AC:

AN:

5178

South Asian (SAS)

AF:

0.0547

AC:

264

AN:

4826

European-Finnish (FIN)

AF:

0.0355

AC:

377

AN:

10616

Middle Eastern (MID)

AF:

0.0612

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0545

AC:

3707

AN:

68012

Other (OTH)

AF:

0.0540

AC:

114

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

405

810

1216

1621

2026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0524

Hom.:

375

Bravo

AF:

0.0560

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.073

(source)

DANN

Benign

0.52

PhyloP100

-0.82

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over