rs546044640

Variant names:

• chrX-41553739-A-C
• rs546044640
• NM_001367721.1:c.2019T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-41553739-A-C
• chrX-41553739-A-G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001367721.1(CASK):​c.2019T>G​(p.Pro673Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,202,486 control chromosomes in the GnomAD database, including 10 homozygotes. There are 871 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (1 hom., 35 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (9 hom. 836 hem.)
• Consequence: CASK NM_001367721.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.23
• 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: 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant X-41553739-A-C is Benign according to our data. Variant chrX-41553739-A-C is described in ClinVar as Benign. ClinVar VariationId is 210582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000616 (69/112017) while in subpopulation SAS AF = 0.0259 (69/2666). AF 95% confidence interval is 0.021. There are 1 homozygotes in GnomAd4. There are 35 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAd4 at 69 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.2019T>G	p.Pro673Pro	synonymous	Exon 21 of 27	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.2019T>G	p.Pro673Pro	synonymous	Exon 21 of 27	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.2001T>G	p.Pro667Pro	synonymous	Exon 20 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.2019T>G	p.Pro673Pro	synonymous	Exon 21 of 27	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.1950T>G	p.Pro650Pro	synonymous	Exon 19 of 25	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.1932T>G	p.Pro644Pro	synonymous	Exon 19 of 25	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes AF: 0.000625 AC: 70 AN: 111963 Hom.: 1 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: 0.0262

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00257 AC: 456 AN: 177142 AF XY: 0.00412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000740

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000128

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00131 AC: 1433 AN: 1090469 Hom.: 9 Cov.: 28 AF XY: 0.00235 AC XY: 836 AN XY: 356249

African (AFR) AF: 0.0000761 AC: 2 AN: 26272

American (AMR) AF: 0.00 AC: 0 AN: 35087

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19316

East Asian (EAS) AF: 0.0000664 AC: 2 AN: 30104

South Asian (SAS) AF: 0.0248 AC: 1330 AN: 53627

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40418

Middle Eastern (MID) AF: 0.000728 AC: 3 AN: 4120

European-Non Finnish (NFE) AF: 0.0000227 AC: 19 AN: 835684

Other (OTH) AF: 0.00168 AC: 77 AN: 45841

GnomAD4 genome AF: 0.000616 AC: 69 AN: 112017 Hom.: 1 Cov.: 23 AF XY: 0.00102 AC XY: 35 AN XY: 34181

African (AFR) AF: 0.00 AC: 0 AN: 30895

American (AMR) AF: 0.00 AC: 0 AN: 10527

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2647

East Asian (EAS) AF: 0.00 AC: 0 AN: 3600

South Asian (SAS) AF: 0.0259 AC: 69 AN: 2666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6053

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53191

Other (OTH) AF: 0.00 AC: 0 AN: 1530

Alfa AF: 0.000202 Hom.: 3

Bravo AF: 0.000159

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	11
DANN	Benign	0.77
PhyloP100		2.2
Mutation Taster		=95/5	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: rs546044640; hg19: chrX-41412992;