rs141790702

Variant names:

• chrX-41609934-G-A
• rs141790702
• NM_001367721.1:c.1125C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001367721.1(CASK):​c.1125C>T​(p.Phe375Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.00071 in 1,206,750 control chromosomes in the GnomAD database, including 7 homozygotes. There are 204 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0039 (4 hom., 93 hem., cov: 23)
  • Exomes 𝑓: 0.00038 (3 hom. 111 hem.)
• Consequence: CASK NM_001367721.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 5.44
• Publications: 0 publications found

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), Ambry Genetics, G2P
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
• X-linked syndromic intellectual disability

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant X-41609934-G-A is Benign according to our data. Variant chrX-41609934-G-A is described in ClinVar as Benign. ClinVar VariationId is 210580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0039 (437/112011) while in subpopulation AFR AF = 0.0135 (418/30883). AF 95% confidence interval is 0.0125. There are 4 homozygotes in GnomAd4. There are 93 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 437 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	NM_001367721.1	MANE Select	c.1125C>T	p.Phe375Phe	synonymous	Exon 12 of 27	NP_001354650.1
	CASK	NM_003688.4		c.1125C>T	p.Phe375Phe	synonymous	Exon 12 of 27	NP_003679.2
	CASK	NM_001410745.1		c.1107C>T	p.Phe369Phe	synonymous	Exon 11 of 26	NP_001397674.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.1125C>T	p.Phe375Phe	synonymous	Exon 12 of 27	ENSP00000367405.1
	CASK	ENST00000421587.8	TSL:1	c.1125C>T	p.Phe375Phe	synonymous	Exon 11 of 25	ENSP00000400526.4
	CASK	ENST00000378166.9	TSL:1	c.1107C>T	p.Phe369Phe	synonymous	Exon 11 of 25	ENSP00000367408.5

Frequencies

GnomAD3 genomes AF: 0.00387 AC: 433 AN: 111956 Hom.: 4 Cov.: 23

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00142

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: 0.0000188

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.00111 AC: 204 AN: 183488 AF XY: 0.000633

Gnomad AFR exome AF: 0.0135

Gnomad AMR exome AF: 0.000656

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000384 AC: 420 AN: 1094739 Hom.: 3 Cov.: 29 AF XY: 0.000308 AC XY: 111 AN XY: 360151

African (AFR) AF: 0.0131 AC: 345 AN: 26327

American (AMR) AF: 0.000653 AC: 23 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19359

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 54057

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40519

Middle Eastern (MID) AF: 0.000485 AC: 2 AN: 4127

European-Non Finnish (NFE) AF: 0.00000954 AC: 8 AN: 839000

Other (OTH) AF: 0.000914 AC: 42 AN: 45972

GnomAD4 genome AF: 0.00390 AC: 437 AN: 112011 Hom.: 4 Cov.: 23 AF XY: 0.00272 AC XY: 93 AN XY: 34195

African (AFR) AF: 0.0135 AC: 418 AN: 30883

American (AMR) AF: 0.00142 AC: 15 AN: 10548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2645

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.00 AC: 0 AN: 2688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6067

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53192

Other (OTH) AF: 0.00196 AC: 3 AN: 1528

Alfa AF: 0.00187 Hom.: 5

Bravo AF: 0.00453

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CASK-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Intellectual disability, CASK-related, X-linked (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	13
DANN	Benign	0.83
PhyloP100		5.4
Mutation Taster		=18/82	polymorphism (auto)

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

Other links and lift over

dbSNP: rs141790702; hg19: chrX-41469187; COSMIC: COSV100587736; COSMIC: COSV100587736;