NM_033056.4:c.3374-14570T>C

Variant names:

• chr10-53917940-A-G
• rs1900451
• NM_033056.4:c.3374-14570T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033056.4(PCDH15):​c.3374-14570T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.69 in 151,948 control chromosomes in the GnomAD database, including 36,758 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.69 (36758 hom., cov: 31)
• Consequence: PCDH15 NM_033056.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.89
• Publications: 4 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, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia
• Usher syndrome type 1

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

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033056.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	NM_033056.4	MANE Plus Clinical	c.3374-14570T>C		intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.3374-14570T>C		intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.3389-14570T>C		intron	N/A	NP_001136235.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCDH15	ENST00000320301.11	TSL:1 MANE Plus Clinical	c.3374-14570T>C		intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.3374-14570T>C		intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.3395-14570T>C		intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.690 AC: 104747 AN: 151830 Hom.: 36736 Cov.: 31

Gnomad AFR AF: 0.607

Gnomad AMI AF: 0.813

Gnomad AMR AF: 0.799

Gnomad ASJ AF: 0.807

Gnomad EAS AF: 0.997

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.713

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.670

Gnomad OTH AF: 0.722

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.690 AC: 104812 AN: 151948 Hom.: 36758 Cov.: 31 AF XY: 0.701 AC XY: 52042 AN XY: 74254

African (AFR) AF: 0.607 AC: 25144 AN: 41434

American (AMR) AF: 0.799 AC: 12200 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.807 AC: 2802 AN: 3470

East Asian (EAS) AF: 0.997 AC: 5136 AN: 5152

South Asian (SAS) AF: 0.821 AC: 3950 AN: 4812

European-Finnish (FIN) AF: 0.713 AC: 7523 AN: 10552

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.670 AC: 45542 AN: 67952

Other (OTH) AF: 0.726 AC: 1531 AN: 2110

Alfa AF: 0.677 Hom.: 4742

Bravo AF: 0.694

Asia WGS AF: 0.895 AC: 3114 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.19
DANN	Benign	0.37
PhyloP100		-2.9
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: rs1900451; hg19: chr10-55677700;