X-18641857-TAAA-TAAAA

Variant names:

• chrX-18641857-T-TA
• rs377648180
• NM_000330.4:c.*146dupT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_000330.4(RS1):​c.*146dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., 58 hem., cov: 20)
  • Exomes 𝑓: 0.036 (0 hom. 5 hem.)
• Consequence: RS1 NM_000330.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.54
• Publications: 0 publications found

Genes affected

RS1 (HGNC:10457): (retinoschisin 1) This gene encodes an extracellular protein that plays a crucial role in the cellular organization of the retina. The encoded protein is assembled and secreted from photoreceptors and bipolar cells as a homo-oligomeric protein complex. Mutations in this gene are responsible for X-linked retinoschisis, a common, early-onset macular degeneration in males that results in a splitting of the inner layers of the retina and severe loss in vision. [provided by RefSeq, Oct 2008]

CDKL5 (HGNC:11411): (cyclin dependent kinase like 5) This gene is a member of Ser/Thr protein kinase family and encodes a phosphorylated protein with protein kinase activity. Mutations in this gene have been associated with X-linked infantile spasm syndrome (ISSX), also known as X-linked West syndrome, and Rett syndrome (RTT). Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]

CDKL5 Gene-Disease associations (from GenCC):

• CDKL5 disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• developmental and epileptic encephalopathy, 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• atypical Rett syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• genetic developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• infantile spasms

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• precocious puberty

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00237 (248/104816) while in subpopulation AFR AF = 0.00614 (178/28993). AF 95% confidence interval is 0.0054. There are 0 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 20. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 58 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000330.4. 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
	RS1	NM_000330.4	MANE Select	c.*146dupT		3_prime_UTR	Exon 6 of 6	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2714-4137dupA		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2714-4137dupA		intron	N/A	NP_003150.1	O76039-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RS1	ENST00000379984.4	TSL:1 MANE Select	c.*146dupT		3_prime_UTR	Exon 6 of 6	ENSP00000369320.3	O15537
	CDKL5	ENST00000379989.6	TSL:1	c.2714-4137dupA		intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2714-4137dupA		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 248 AN: 104811 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00173

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00118

Gnomad SAS AF: 0.00120

Gnomad FIN AF: 0.00297

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000593

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.0363 AC: 11189 AN: 307928 Hom.: 0 Cov.: 0 AF XY: 0.0000568 AC XY: 5 AN XY: 88084

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0308 AC: 264 AN: 8585

American (AMR) AF: 0.0333 AC: 396 AN: 11909

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 287 AN: 8375

East Asian (EAS) AF: 0.0329 AC: 500 AN: 15196

South Asian (SAS) AF: 0.0215 AC: 461 AN: 21486

European-Finnish (FIN) AF: 0.0368 AC: 586 AN: 15913

Middle Eastern (MID) AF: 0.0333 AC: 35 AN: 1050

European-Non Finnish (NFE) AF: 0.0385 AC: 8049 AN: 209268

Other (OTH) AF: 0.0378 AC: 611 AN: 16146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00237 AC: 248 AN: 104816 Hom.: 0 Cov.: 20 AF XY: 0.00196 AC XY: 58 AN XY: 29606

African (AFR) AF: 0.00614 AC: 178 AN: 28993

American (AMR) AF: 0.00173 AC: 17 AN: 9817

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2542

East Asian (EAS) AF: 0.00118 AC: 4 AN: 3389

South Asian (SAS) AF: 0.00121 AC: 3 AN: 2474

European-Finnish (FIN) AF: 0.00297 AC: 14 AN: 4706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 205

European-Non Finnish (NFE) AF: 0.000593 AC: 30 AN: 50623

Other (OTH) AF: 0.00142 AC: 2 AN: 1409

Alfa AF: 0.00 Hom.: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

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: rs377648180; hg19: chrX-18659977;