10-54132840-TACACACACACAC-TACACACACAC

Variant names:

• chr10-54132840-TAC-T
• rs5785040
• NM_033056.4:c.1917+33_1917+34delGT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001384140.1(PCDH15):​c.1917+33_1917+34delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0361 in 1,371,676 control chromosomes in the GnomAD database, including 795 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (233 hom., cov: 0)
  • Exomes 𝑓: 0.035 (562 hom.)
• Consequence: PCDH15 NM_001384140.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0900

Genes affected

PCDH15 (HGNC:14674): (protocadherin related 15) This gene is a member of the cadherin superfamily. Family members encode integral membrane proteins that mediate calcium-dependent cell-cell adhesion. It plays an essential role in maintenance of normal retinal and cochlear function. Mutations in this gene result in hearing loss and Usher Syndrome Type IF (USH1F). Extensive alternative splicing resulting in multiple isoforms has been observed in the mouse ortholog. Similar alternatively spliced transcripts are inferred to occur in human, and additional variants are likely to occur. [provided by RefSeq, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 10-54132840-TAC-T is Benign according to our data. Variant chr10-54132840-TAC-T is described in ClinVar as [Benign]. Clinvar id is 227006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-54132840-TAC-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0871 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.1917+33_1917+34delGT		intron_variant	Intron 15 of 32	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.1917+33_1917+34delGT		intron_variant	Intron 15 of 37	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.1917+33_1917+34delGT		intron_variant	Intron 15 of 32	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.1917+33_1917+34delGT		intron_variant	Intron 15 of 37		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6758 AN: 150298 Hom.: 233 Cov.: 0

Gnomad AFR AF: 0.0896

Gnomad AMI AF: 0.00554

Gnomad AMR AF: 0.0311

Gnomad ASJ AF: 0.0348

Gnomad EAS AF: 0.00157

Gnomad SAS AF: 0.0483

Gnomad FIN AF: 0.0276

Gnomad MID AF: 0.0865

Gnomad NFE AF: 0.0274

Gnomad OTH AF: 0.0538

GnomAD3 exomes AF: 0.0497 AC: 6969 AN: 140090 Hom.: 132 AF XY: 0.0508 AC XY: 3756 AN XY: 73980

Gnomad AFR exome AF: 0.124

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0536

Gnomad EAS exome AF: 0.00372

Gnomad SAS exome AF: 0.0697

Gnomad FIN exome AF: 0.0424

Gnomad NFE exome AF: 0.0475

Gnomad OTH exome AF: 0.0543

GnomAD4 exome AF: 0.0351 AC: 42815 AN: 1221270 Hom.: 562 AF XY: 0.0359 AC XY: 21703 AN XY: 604248

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.0267

Gnomad4 ASJ exome AF: 0.0467

Gnomad4 EAS exome AF: 0.00134

Gnomad4 SAS exome AF: 0.0587

Gnomad4 FIN exome AF: 0.0338

Gnomad4 NFE exome AF: 0.0318

Gnomad4 OTH exome AF: 0.0408

GnomAD4 genome AF: 0.0450 AC: 6764 AN: 150406 Hom.: 233 Cov.: 0 AF XY: 0.0446 AC XY: 3276 AN XY: 73418

Gnomad4 AFR AF: 0.0895

Gnomad4 AMR AF: 0.0311

Gnomad4 ASJ AF: 0.0348

Gnomad4 EAS AF: 0.00157

Gnomad4 SAS AF: 0.0485

Gnomad4 FIN AF: 0.0276

Gnomad4 NFE AF: 0.0274

Gnomad4 OTH AF: 0.0532

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Dec 08, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

c.1917+13GT[10] in intron 15 of PCDH15: This variant is not expected to have cli nical significance because it is not located within the splice consensus sequenc e. It has been detected in 8.9% (4209/47276) of chromosomes across several diver se populations by the Exome Aggregate Consortium (http://exac.broadinstitute.org /variant/10-55892600-TAC-T). -

Autosomal recessive nonsyndromic hearing loss 23 Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Usher syndrome type 1F Benign:1

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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: rs5785040; hg19: chr10-55892600;