rs767030499

Variant names:

• chrX-41542798-G-A
• rs767030499
• NM_001367721.1:c.2048C>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BS2

The NM_001367721.1(CASK):​c.2048C>T​(p.Ala683Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,030,795 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000029 (0 hom. 3 hem.)
• Consequence: CASK NM_001367721.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.48

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP2: Missense variant in the CASK gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 30 curated pathogenic missense variants (we use a threshold of 10). The gene has 23 curated benign missense variants. Gene score misZ: 4.2502 (above the threshold of 3.09). GenCC associations: The gene is linked to syndromic X-linked intellectual disability Najm type, X-linked syndromic intellectual disability, developmental and epileptic encephalopathy, FG syndrome 4.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASK	NM_001367721.1	c.2048C>T	p.Ala683Val	missense_variant	Exon 22 of 27	ENST00000378163.7	NP_001354650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASK	ENST00000378163.7	c.2048C>T	p.Ala683Val	missense_variant	Exon 22 of 27	5	NM_001367721.1	ENSP00000367405.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000547 AC: 1 AN: 182835 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67325

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000291 AC: 3 AN: 1030795 Hom.: 0 Cov.: 24 AF XY: 0.00000981 AC XY: 3 AN XY: 305773

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000569

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000128

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, CASK-related, X-linked Uncertain:1

Apr 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 537748). This variant has not been reported in the literature in individuals affected with CASK-related conditions. This variant is present in population databases (rs767030499, gnomAD 0.004%), including at least one homozygous and/or hemizygous individual. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 683 of the CASK protein (p.Ala683Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	.;.;.;.;.;.;.;D;.;.;.;.;.;.;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Pathogenic	3.1	.;.;.;M;.;.;.;M;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.4	.;.;.;.;.;D;.;D;.;.;.;.;.;.;.
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	.;.;.;.;.;D;.;D;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0030	.;.;.;.;.;D;.;D;.;.;.;.;.;.;.
Polyphen		0.96	D;P;.;D;.;D;.;D;.;.;.;.;.;.;.
Vest4		0.72
MutPred		0.39		.;.;.;Gain of catalytic residue at A683 (P = 0.0148);.;.;.;Gain of catalytic residue at A683 (P = 0.0148);.;.;.;.;.;.;.;
MVP		0.99
MPC		2.2
ClinPred		0.92	D
GERP RS		5.6
Varity_R		0.87
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs767030499; hg19: chrX-41402051;