rs41274636

Variant names:

• chr10-54527809-T-C
• rs41274636
• NM_033056.4:c.157+3A>G

Your query was ambiguous. Multiple possible variants found:

• chr10-54527809-T-C
• chr10-54527809-T-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033056.4(PCDH15):​c.157+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0838 in 1,603,330 control chromosomes in the GnomAD database, including 5,925 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.094 (702 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5223 hom.)
• Consequence: PCDH15 NM_033056.4 splice_region, intron
• Scores: Splicing: ADA: 0.001148
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.746
• Publications: 9 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

ENSG00000234173 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant 10-54527809-T-C is Benign according to our data. Variant chr10-54527809-T-C is described in ClinVar as Benign. ClinVar VariationId is 46444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 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.157+3A>G		splice_region intron	N/A	NP_149045.3
	PCDH15	NM_001384140.1	MANE Select	c.157+3A>G		splice_region intron	N/A	NP_001371069.1
	PCDH15	NM_001142763.2		c.172+3A>G		splice_region 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.157+3A>G		splice_region intron	N/A	ENSP00000322604.6
	PCDH15	ENST00000644397.2	MANE Select	c.157+3A>G		splice_region intron	N/A	ENSP00000495195.1
	PCDH15	ENST00000395445.6	TSL:1	c.157+3A>G		splice_region intron	N/A	ENSP00000378832.2

Frequencies

GnomAD3 genomes AF: 0.0937 AC: 14225 AN: 151842 Hom.: 696 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.0603

Gnomad AMR AF: 0.0689

Gnomad ASJ AF: 0.0514

Gnomad EAS AF: 0.0832

Gnomad SAS AF: 0.0570

Gnomad FIN AF: 0.0606

Gnomad MID AF: 0.0924

Gnomad NFE AF: 0.0839

Gnomad OTH AF: 0.0872

GnomAD2 exomes AF: 0.0782 AC: 19457 AN: 248754 AF XY: 0.0761

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0646

Gnomad ASJ exome AF: 0.0501

Gnomad EAS exome AF: 0.0740

Gnomad FIN exome AF: 0.0654

Gnomad NFE exome AF: 0.0860

Gnomad OTH exome AF: 0.0842

GnomAD4 exome AF: 0.0827 AC: 120086 AN: 1451368 Hom.: 5223 Cov.: 30 AF XY: 0.0818 AC XY: 59065 AN XY: 722368

African (AFR) AF: 0.141 AC: 4667 AN: 33176

American (AMR) AF: 0.0662 AC: 2927 AN: 44216

Ashkenazi Jewish (ASJ) AF: 0.0505 AC: 1310 AN: 25936

East Asian (EAS) AF: 0.0830 AC: 3285 AN: 39590

South Asian (SAS) AF: 0.0551 AC: 4693 AN: 85202

European-Finnish (FIN) AF: 0.0639 AC: 3407 AN: 53302

Middle Eastern (MID) AF: 0.0827 AC: 474 AN: 5734

European-Non Finnish (NFE) AF: 0.0853 AC: 94205 AN: 1104228

Other (OTH) AF: 0.0853 AC: 5118 AN: 59984

GnomAD4 genome AF: 0.0938 AC: 14252 AN: 151962 Hom.: 702 Cov.: 32 AF XY: 0.0914 AC XY: 6794 AN XY: 74300

African (AFR) AF: 0.138 AC: 5718 AN: 41474

American (AMR) AF: 0.0687 AC: 1047 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.0514 AC: 178 AN: 3464

East Asian (EAS) AF: 0.0834 AC: 429 AN: 5142

South Asian (SAS) AF: 0.0577 AC: 278 AN: 4820

European-Finnish (FIN) AF: 0.0606 AC: 643 AN: 10608

Middle Eastern (MID) AF: 0.0890 AC: 26 AN: 292

European-Non Finnish (NFE) AF: 0.0839 AC: 5697 AN: 67894

Other (OTH) AF: 0.0858 AC: 181 AN: 2110

Alfa AF: 0.0878 Hom.: 493

Bravo AF: 0.0979

Asia WGS AF: 0.0800 AC: 278 AN: 3472

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Usher syndrome type 1F (2)
-	-	1	Usher syndrome type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.81
PhyloP100		0.75
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0011
dbscSNV1_RF	Benign	0.034
SpliceAI score (max)		0.010		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: rs41274636; hg19: chr10-56287569; COSMIC: COSV57391208;