Genetic Variant NM_020356.4:c.643-134C>G (chr20-56451685-C-G) – 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.643-134C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.413 in 674,394 control chromosomes in the GnomAD database, including 61,260 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 0.48 ( 19341 hom., cov: 31)

Exomes 𝑓: 0.39 ( 41919 hom. )

Consequence

CASS4
NM_020356.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.125

Publications

6 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=-0.9).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.707 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
CASS4	NM_020356.4	MANE Select	c.643-134C>G	intron	N/A	NP_065089.2
CASS4	NM_001164116.2		c.643-134C>G	intron	N/A	NP_001157588.1
CASS4	NM_001164114.2		c.481-134C>G	intron	N/A	NP_001157586.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
CASS4	ENST00000679887.1	MANE Select	c.643-134C>G	intron	N/A	ENSP00000506506.1
CASS4	ENST00000360314.7	TSL:1	c.643-134C>G	intron	N/A	ENSP00000353462.3
CASS4	ENST00000497244.1	TSL:1	n.794-134C>G	intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.482

AC:

73131

AN:

151838

Hom.:

19293

Cov.:

show subpopulations

Gnomad AFR

AF:

0.713

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.365

Gnomad EAS

AF:

0.536

Gnomad SAS

AF:

0.370

Gnomad FIN

AF:

0.459

Gnomad MID

AF:

0.386

Gnomad NFE

AF:

0.367

Gnomad OTH

AF:

0.423

GnomAD4 exome

AF:

0.393

AC:

205316

AN:

522438

Hom.:

41919

AF XY:

0.389

AC XY:

106258

AN XY:

273438

show subpopulations

African (AFR)

AF:

0.710

AC:

9821

AN:

13836

American (AMR)

AF:

0.441

AC:

8516

AN:

19320

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

5112

AN:

14180

East Asian (EAS)

AF:

0.533

AC:

17081

AN:

32046

South Asian (SAS)

AF:

0.348

AC:

16046

AN:

46082

European-Finnish (FIN)

AF:

0.442

AC:

17090

AN:

38696

Middle Eastern (MID)

AF:

0.389

AC:

809

AN:

2082

European-Non Finnish (NFE)

AF:

0.365

AC:

119590

AN:

327770

Other (OTH)

AF:

0.396

AC:

11251

AN:

28426

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

6166

12333

18499

24666

30832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1394

2788

4182

5576

6970

<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:

0.482

AC:

73241

AN:

151956

Hom.:

19341

Cov.:

AF XY:

0.483

AC XY:

35846

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.714

AC:

29575

AN:

41438

American (AMR)

AF:

0.446

AC:

6805

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.365

AC:

1266

AN:

3466

East Asian (EAS)

AF:

0.536

AC:

2764

AN:

5154

South Asian (SAS)

AF:

0.369

AC:

1783

AN:

4826

European-Finnish (FIN)

AF:

0.459

AC:

4839

AN:

10540

Middle Eastern (MID)

AF:

0.401

AC:

118

AN:

294

European-Non Finnish (NFE)

AF:

0.367

AC:

24957

AN:

67952

Other (OTH)

AF:

0.423

AC:

892

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1774

3548

5322

7096

8870

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

636

1272

1908

2544

3180

<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:

0.277

Hom.:

629

Bravo

AF:

0.491

Asia WGS

AF:

0.414

AC:

1442

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

1.3

(source)

DANN

Benign

0.64

PhyloP100

-0.13

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