rs373431768

Variant names:

• chrX-41745577-A-G
• rs373431768
• NM_001367721.1:c.303T>C
• CASK p.Phe101Phe

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001367721.1(CASK):​c.303T>C​(p.Phe101Phe) variant causes a synonymous change. The variant allele was found at a frequency of 0.00000417 in 1,200,083 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
• Consequence: CASK NM_001367721.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.16
• 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), G2P, Ambry Genetics
• syndromic X-linked intellectual disability Najm type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-41745577-A-G is Benign according to our data. Variant chrX-41745577-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 537754.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 AD,XL 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	NM_001367721.1	MANE Select	c.303T>C	p.Phe101Phe	synonymous	Exon 4 of 27	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.303T>C	p.Phe101Phe	synonymous	Exon 4 of 27	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.303T>C	p.Phe101Phe	synonymous	Exon 4 of 26	NP_001397674.1	A0A2R8YE77

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASK	ENST00000378163.7	TSL:5 MANE Select	c.303T>C	p.Phe101Phe	synonymous	Exon 4 of 27	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.321T>C	p.Phe107Phe	synonymous	Exon 4 of 25	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.303T>C	p.Phe101Phe	synonymous	Exon 4 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112277 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000375

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000166 AC: 3 AN: 181014 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000373

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1087806 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 353654

African (AFR) AF: 0.00 AC: 0 AN: 26220

American (AMR) AF: 0.00 AC: 0 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19313

East Asian (EAS) AF: 0.00 AC: 0 AN: 30142

South Asian (SAS) AF: 0.00 AC: 0 AN: 53722

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40498

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.00000360 AC: 3 AN: 832859

Other (OTH) AF: 0.00 AC: 0 AN: 45762

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112277 Hom.: 0 Cov.: 23 AF XY: 0.0000581 AC XY: 2 AN XY: 34439

African (AFR) AF: 0.00 AC: 0 AN: 30852

American (AMR) AF: 0.00 AC: 0 AN: 10569

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3603

South Asian (SAS) AF: 0.00 AC: 0 AN: 2749

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6113

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53304

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.000130 Hom.: 1

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability, CASK-related, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_noAF	Benign	-0.43
CADD	Benign	13
DANN	Benign	0.79
PhyloP100		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs373431768;

hg19: chrX-41604830;