NM_001367721.1:c.1034-6C>T

Variant names:

• chrX-41610031-G-A
• rs73470569
• NM_001367721.1:c.1034-6C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001367721.1(CASK):​c.1034-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0164 in 1,207,117 control chromosomes in the GnomAD database, including 2,092 homozygotes. There are 5,240 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.085 (1048 hom., 2555 hem., cov: 23)
  • Exomes 𝑓: 0.0094 (1044 hom. 2685 hem.)
• Consequence: CASK NM_001367721.1 splice_region, intron
• Scores: Splicing: ADA: 0.00009656
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.827
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant X-41610031-G-A is Benign according to our data. Variant chrX-41610031-G-A is described in ClinVar as Benign. ClinVar VariationId is 94374.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

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.1034-6C>T		splice_region intron	N/A	NP_001354650.1	O14936-1
	CASK	NM_003688.4		c.1034-6C>T		splice_region intron	N/A	NP_003679.2	O14936-2
	CASK	NM_001410745.1		c.1016-6C>T		splice_region intron	N/A	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.1034-6C>T		splice_region intron	N/A	ENSP00000367405.1	O14936-1
	CASK	ENST00000421587.8	TSL:1	c.1034-6C>T		splice_region intron	N/A	ENSP00000400526.4	A0A7I2RJN6
	CASK	ENST00000378166.9	TSL:1	c.1016-6C>T		splice_region intron	N/A	ENSP00000367408.5	A0A2U3TZM4

Frequencies

GnomAD3 genomes AF: 0.0851 AC: 9472 AN: 111337 Hom.: 1047 Cov.: 23

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00225

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0169

Gnomad NFE AF: 0.000828

Gnomad OTH AF: 0.0537

GnomAD2 exomes AF: 0.0247 AC: 4444 AN: 179855 AF XY: 0.0153

Gnomad AFR exome AF: 0.305

Gnomad AMR exome AF: 0.0147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000576

Gnomad OTH exome AF: 0.0128

GnomAD4 exome AF: 0.00936 AC: 10255 AN: 1095725 Hom.: 1044 Cov.: 29 AF XY: 0.00743 AC XY: 2685 AN XY: 361159

African (AFR) AF: 0.314 AC: 8268 AN: 26335

American (AMR) AF: 0.0169 AC: 593 AN: 35088

Ashkenazi Jewish (ASJ) AF: 0.0000517 AC: 1 AN: 19339

East Asian (EAS) AF: 0.00 AC: 0 AN: 30144

South Asian (SAS) AF: 0.000910 AC: 49 AN: 53869

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40428

Middle Eastern (MID) AF: 0.0136 AC: 56 AN: 4132

European-Non Finnish (NFE) AF: 0.000397 AC: 334 AN: 840413

Other (OTH) AF: 0.0207 AC: 954 AN: 45977

GnomAD4 genome AF: 0.0851 AC: 9482 AN: 111392 Hom.: 1048 Cov.: 23 AF XY: 0.0760 AC XY: 2555 AN XY: 33632

African (AFR) AF: 0.298 AC: 9071 AN: 30468

American (AMR) AF: 0.0265 AC: 278 AN: 10479

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3585

South Asian (SAS) AF: 0.00150 AC: 4 AN: 2664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5994

Middle Eastern (MID) AF: 0.0186 AC: 4 AN: 215

European-Non Finnish (NFE) AF: 0.000828 AC: 44 AN: 53134

Other (OTH) AF: 0.0531 AC: 81 AN: 1526

Alfa AF: 0.0452 Hom.: 303

Bravo AF: 0.0987

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	not provided (2)
-	-	1	Intellectual disability, CASK-related, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	6.9
DANN	Benign	0.60
PhyloP100		0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000097
dbscSNV1_RF	Benign	0.0060
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: rs73470569; hg19: chrX-41469284;