X-18641857-TA-T

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

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]

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RS1	NM_000330.4	c.*146delT		3_prime_UTR_variant	Exon 6 of 6	ENST00000379984.4	NP_000321.1
RS1	XM_047442337.1	c.*146delT		3_prime_UTR_variant	Exon 4 of 4		XP_047298293.1
CDKL5	NM_001037343.2	c.2714-4137delA		intron_variant	Intron 19 of 21		NP_001032420.1
CDKL5	NM_003159.3	c.2714-4137delA		intron_variant	Intron 18 of 20		NP_003150.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RS1	ENST00000379984	c.*146delT		3_prime_UTR_variant	Exon 6 of 6	1	NM_000330.4	ENSP00000369320.3
CDKL5	ENST00000379989.6	c.2714-4137delA		intron_variant	Intron 19 of 21	1		ENSP00000369325.3
CDKL5	ENST00000379996.7	c.2714-4137delA		intron_variant	Intron 18 of 20	1		ENSP00000369332.3
RS1	ENST00000476595.1	n.*66delT		downstream_gene_variant		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

Gnomad4 AFR exome AF: 0.284 AC: 2077 AN: 7312

Gnomad4 AMR exome AF: 0.180 AC: 1732 AN: 9640

Gnomad4 ASJ exome AF: 0.175 AC: 1197 AN: 6857

Gnomad4 EAS exome AF: 0.153 AC: 1769 AN: 11556

Gnomad4 SAS exome AF: 0.0977 AC: 1600 AN: 16376

Gnomad4 FIN exome AF: 0.148 AC: 1882 AN: 12754

Gnomad4 NFE exome AF: 0.138 AC: 24340 AN: 175804

Gnomad4 Remaining exome AF: 0.163 AC: 2144 AN: 13119

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (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

Gnomad4 AFR AF: 0.156 AC: 0.156194 AN: 0.156194

Gnomad4 AMR AF: 0.0157 AC: 0.0157287 AN: 0.0157287

Gnomad4 ASJ AF: 0.0300 AC: 0.0300277 AN: 0.0300277

Gnomad4 EAS AF: 0.000296 AC: 0.000295508 AN: 0.000295508

Gnomad4 SAS AF: 0.00526 AC: 0.00525677 AN: 0.00525677

Gnomad4 FIN AF: 0.00862 AC: 0.00862255 AN: 0.00862255

Gnomad4 NFE AF: 0.00594 AC: 0.00593824 AN: 0.00593824

Gnomad4 OTH AF: 0.0468 AC: 0.0468085 AN: 0.0468085

Alfa AF: 0.00116 Hom.: 7

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 05, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs377648180; hg19: chrX-18659977; COSMIC: COSV66107353; COSMIC: COSV66107353;