Genetic Variant NM_001367721.1:c.2297G>A (chrX-41534726-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001367721.1(CASK):c.2297G>A(p.Arg766Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,205,208 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 37 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R766W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.000065 ( 0 hom. 27 hem. )

Consequence

CASK
NM_001367721.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 7.57

Publications

1 publications found

Variant links:

Genes affected

CASK (HGNC:1497): (calcium/calmodulin dependent serine protein kinase) This gene encodes a calcium/calmodulin-dependent serine protein kinase. The encoded protein is a MAGUK (membrane-associated guanylate kinase) protein family member. These proteins are scaffold proteins and the encoded protein is located at synapses in the brain. Mutations in this gene are associated with FG syndrome 4, intellectual disability and microcephaly with pontine and cerebellar hypoplasia, and a form of X-linked intellectual disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

CASK Gene-Disease associations (from GenCC):

FG syndrome 4
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
syndromic X-linked intellectual disability Najm type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet, Ambry Genetics
X-linked syndromic intellectual disability
Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
genetic developmental and epileptic encephalopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CASK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039138973).

BP6

Variant X-41534726-C-T is Benign according to our data. Variant chrX-41534726-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 282560.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000512 (57/111347) while in subpopulation AFR AF = 0.00163 (50/30708). AF 95% confidence interval is 0.00127. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 57 XL,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001367721.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASK	NM_001367721.1	MANE Select	c.2297G>A	p.Arg766Gln	missense	Exon 24 of 27	NP_001354650.1	O14936-1
CASK	NM_003688.4		c.2282G>A	p.Arg761Gln	missense	Exon 24 of 27	NP_003679.2	O14936-2
CASK	NM_001410745.1		c.2279G>A	p.Arg760Gln	missense	Exon 23 of 26	NP_001397674.1	A0A2R8YE77

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASK	ENST00000378163.7	TSL:5 MANE Select	c.2297G>A	p.Arg766Gln	missense	Exon 24 of 27	ENSP00000367405.1	O14936-1
CASK	ENST00000421587.8	TSL:1	c.2228G>A	p.Arg743Gln	missense	Exon 22 of 25	ENSP00000400526.4	A0A7I2RJN6
CASK	ENST00000378166.9	TSL:1	c.2195G>A	p.Arg732Gln	missense	Exon 22 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes

AF:

0.000512

AC:

AN:

111295

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000754

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000164

AC:

AN:

183446

AF XY:

0.000147

show subpopulations

Gnomad AFR exome

AF:

0.00152

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000649

AC:

AN:

1093861

Hom.:

Cov.:

AF XY:

0.0000751

AC XY:

AN XY:

359445

show subpopulations

African (AFR)

AF:

0.00148

AC:

AN:

26329

American (AMR)

AF:

0.000142

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.0000517

AC:

AN:

19350

East Asian (EAS)

AF:

0.00

AC:

AN:

30179

South Asian (SAS)

AF:

0.0000185

AC:

AN:

54036

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40502

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.0000239

AC:

AN:

838195

Other (OTH)

AF:

0.000109

AC:

AN:

45945

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.000512

AC:

AN:

111347

Hom.:

Cov.:

AF XY:

0.000298

AC XY:

AN XY:

33593

show subpopulations

African (AFR)

AF:

0.00163

AC:

AN:

30708

American (AMR)

AF:

0.000287

AC:

AN:

10445

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2627

East Asian (EAS)

AF:

0.00

AC:

AN:

3571

South Asian (SAS)

AF:

0.00

AC:

AN:

2678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5883

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000755

AC:

AN:

53011

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000208

Hom.:

Bravo

AF:

0.000570

ESP6500AA

AF:

0.00183

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000189

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CASK-related disorder (1)

Inborn genetic diseases (1)

Intellectual disability, CASK-related, X-linked (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.082

MetaRNN

Benign

0.039

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.9

PhyloP100

7.6

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.0

REVEL

Benign

0.23

Sift

Benign

0.047

Sift4G

Benign

0.25

Polyphen

0.75

Vest4

0.26

MVP

0.86

MPC

1.3

ClinPred

0.046

GERP RS

5.3

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.40

gMVP

0.81

Mutation Taster

=89/11

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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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