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. The variant received -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
• Publications: 2 publications found

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]

PCDH15 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 23

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• Usher syndrome type 1

  Inheritance: AR, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Usher syndrome type 1F

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 227006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0871 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384140.1. 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
	PCDH15	NM_033056.4	MANE Plus Clinical	c.1917+33_1917+34delGT		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.1917+33_1917+34delGT		intron	N/A	NP_001371069.1	Q96QU1-7
	PCDH15	NM_001142763.2		c.1932+33_1932+34delGT		intron	N/A	NP_001136235.1	A2A3D8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.1917+33_1917+34delGT		intron	N/A	ENSP00000322604.6	Q96QU1-1
	PCDH15	ENST00000644397.2	MANE Select	c.1917+33_1917+34delGT		intron	N/A	ENSP00000495195.1	Q96QU1-7
	PCDH15	ENST00000395445.6	TSL:1	c.1938+33_1938+34delGT		intron	N/A	ENSP00000378832.2	Q96QU1-4

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

GnomAD2 exomes AF: 0.0497 AC: 6969 AN: 140090 AF XY: 0.0508

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 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

African (AFR) AF: 0.109 AC: 3037 AN: 27934

American (AMR) AF: 0.0267 AC: 892 AN: 33430

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 973 AN: 20822

East Asian (EAS) AF: 0.00134 AC: 46 AN: 34262

South Asian (SAS) AF: 0.0587 AC: 4136 AN: 70456

European-Finnish (FIN) AF: 0.0338 AC: 1469 AN: 43424

Middle Eastern (MID) AF: 0.0825 AC: 417 AN: 5054

European-Non Finnish (NFE) AF: 0.0318 AC: 29774 AN: 935136

Other (OTH) AF: 0.0408 AC: 2071 AN: 50752

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

African (AFR) AF: 0.0895 AC: 3666 AN: 40960

American (AMR) AF: 0.0311 AC: 469 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.0348 AC: 120 AN: 3444

East Asian (EAS) AF: 0.00157 AC: 8 AN: 5082

South Asian (SAS) AF: 0.0485 AC: 231 AN: 4760

European-Finnish (FIN) AF: 0.0276 AC: 284 AN: 10308

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0274 AC: 1846 AN: 67470

Other (OTH) AF: 0.0532 AC: 111 AN: 2086

Alfa AF: 0.0649 Hom.: 79

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive nonsyndromic hearing loss 23 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Usher syndrome type 1F (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.090
Mutation Taster		=100/0	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: rs5785040; hg19: chr10-55892600;