rs377648180

Variant names:

• chrX-18641857-TAAA-T
• rs377648180
• NM_000330.4:c.*144_*146delTTT

Your query was ambiguous. Multiple possible variants found:

• chrX-18641857-TAAA-T
• chrX-18641857-TAAA-TA
• chrX-18641857-TAAA-TAA
• chrX-18641857-TAAA-TAAAA
• chrX-18641857-TAAA-TAAAAA

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000330.4(RS1):​c.*144_*146delTTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 451,677 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000095 (0 hom., 0 hem., cov: 20)
  • Exomes 𝑓: 0.000017 (0 hom. 3 hem.)
• Consequence: RS1 NM_000330.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 3 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.*144_*146delTTT		3_prime_UTR	Exon 6 of 6	NP_000321.1	O15537
	CDKL5	NM_001037343.2		c.2714-4139_2714-4137delAAA		intron	N/A	NP_001032420.1	O76039-1
	CDKL5	NM_003159.3		c.2714-4139_2714-4137delAAA		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.*144_*146delTTT		3_prime_UTR	Exon 6 of 6	ENSP00000369320.3	O15537
	CDKL5	ENST00000379989.6	TSL:1	c.2714-4139_2714-4137delAAA		intron	N/A	ENSP00000369325.3	O76039-1
	CDKL5	ENST00000379996.7	TSL:1	c.2714-4139_2714-4137delAAA		intron	N/A	ENSP00000369332.3	O76039-1

Frequencies

GnomAD3 genomes AF: 0.00000954 AC: 1 AN: 104875 Hom.: 0 Cov.: 20

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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000197

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000173 AC: 6 AN: 346802 Hom.: 0 AF XY: 0.0000279 AC XY: 3 AN XY: 107578

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

African (AFR) AF: 0.00 AC: 0 AN: 9446

American (AMR) AF: 0.00 AC: 0 AN: 13596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9575

East Asian (EAS) AF: 0.00 AC: 0 AN: 17818

South Asian (SAS) AF: 0.00 AC: 0 AN: 24721

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18067

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1222

European-Non Finnish (NFE) AF: 0.0000256 AC: 6 AN: 234076

Other (OTH) AF: 0.00 AC: 0 AN: 18281

⚠️ 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: 0.00000954 AC: 1 AN: 104875 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 29619

African (AFR) AF: 0.00 AC: 0 AN: 28952

American (AMR) AF: 0.00 AC: 0 AN: 9813

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 3403

South Asian (SAS) AF: 0.00 AC: 0 AN: 2495

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4733

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 229

European-Non Finnish (NFE) AF: 0.0000197 AC: 1 AN: 50654

Other (OTH) AF: 0.00 AC: 0 AN: 1396

Alfa AF: 0.00 Hom.: 7

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

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;