NM_000330.4:c.*146delT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000330.4(RS1):​c.*146delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.050 (293 hom., 1231 hem., cov: 20)
  • Exomes 𝑓: 0.14 (49 hom. 345 hem.)
• Consequence: RS1 NM_000330.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant X-18641857-TA-T is Benign according to our data. Variant chrX-18641857-TA-T is described in ClinVar as Benign. ClinVar VariationId is 1272473.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.152 is higher than 0.05.

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.*146delT		3_prime_UTR	Exon 6 of 6	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2714-4137delA		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2714-4137delA		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.*146delT		3_prime_UTR	Exon 6 of 6	ENSP00000369320.3	O15537
	CDKL5	ENST00000379989.6	TSL:1	c.2714-4137delA		intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2714-4137delA		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.0496 AC: 5188 AN: 104570 Hom.: 292 Cov.: 20

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0157

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.000294

Gnomad SAS AF: 0.00481

Gnomad FIN AF: 0.00862

Gnomad MID AF: 0.0482

Gnomad NFE AF: 0.00598

Gnomad OTH AF: 0.0473

GnomAD4 exome AF: 0.145 AC: 36862 AN: 254271 Hom.: 49 Cov.: 0 AF XY: 0.00556 AC XY: 345 AN XY: 62017

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

African (AFR) AF: 0.284 AC: 2077 AN: 7312

American (AMR) AF: 0.180 AC: 1732 AN: 9640

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 1197 AN: 6857

East Asian (EAS) AF: 0.153 AC: 1769 AN: 11556

South Asian (SAS) AF: 0.0977 AC: 1600 AN: 16376

European-Finnish (FIN) AF: 0.148 AC: 1882 AN: 12754

Middle Eastern (MID) AF: 0.142 AC: 121 AN: 853

European-Non Finnish (NFE) AF: 0.138 AC: 24340 AN: 175804

Other (OTH) AF: 0.163 AC: 2144 AN: 13119

⚠️ 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: 0.0496 AC: 5185 AN: 104574 Hom.: 293 Cov.: 20 AF XY: 0.0417 AC XY: 1231 AN XY: 29522

African (AFR) AF: 0.156 AC: 4524 AN: 28964

American (AMR) AF: 0.0157 AC: 154 AN: 9791

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 76 AN: 2531

East Asian (EAS) AF: 0.000296 AC: 1 AN: 3384

South Asian (SAS) AF: 0.00526 AC: 13 AN: 2473

European-Finnish (FIN) AF: 0.00862 AC: 40 AN: 4639

Middle Eastern (MID) AF: 0.0539 AC: 11 AN: 204

European-Non Finnish (NFE) AF: 0.00594 AC: 300 AN: 50520

Other (OTH) AF: 0.0468 AC: 66 AN: 1410

Alfa AF: 0.00116 Hom.: 7

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5
Mutation Taster		=99/1	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: rs377648180; hg19: chrX-18659977; COSMIC: COSV66107353; COSMIC: COSV66107353;