10-54664208-A-T

Variant names:

• chr10-54664208-A-T
• rs11004439
• NM_033056.4:c.55T>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_001384140.1(PCDH15):​c.55T>A​(p.Ser19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S19A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PCDH15 NM_001384140.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.188

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10997331).
• BP6: Variant 10-54664208-A-T is Benign according to our data. Variant chr10-54664208-A-T is described in ClinVar as [Benign]. Clinvar id is 2413859.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-54664208-A-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCDH15	NM_033056.4	c.55T>A	p.Ser19Thr	missense_variant	Exon 2 of 33	ENST00000320301.11	NP_149045.3
PCDH15	NM_001384140.1	c.55T>A	p.Ser19Thr	missense_variant	Exon 2 of 38	ENST00000644397.2	NP_001371069.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCDH15	ENST00000320301.11	c.55T>A	p.Ser19Thr	missense_variant	Exon 2 of 33	1	NM_033056.4	ENSP00000322604.6
PCDH15	ENST00000644397.2	c.55T>A	p.Ser19Thr	missense_variant	Exon 2 of 38		NM_001384140.1	ENSP00000495195.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250098 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460042 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726310

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	1.0
DANN	Benign	0.69
DEOGEN2	Benign	0.010	T;.;.;.;.;T;.;.;T;.;T;.;.;T;.;T;.;.;.;.;.;.;T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.58	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.11	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	.;.;.;.;N;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;N;N;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.32	N;.;.;N;.;.;N;N;.;N;.;N;N;.;N;.;.;N;N;N;N;N;N;N;.;N
REVEL	Benign	0.031
Sift	Benign	0.20	T;.;.;T;.;.;T;T;.;T;.;T;T;.;T;.;.;T;T;T;T;T;T;T;.;T
Sift4G	Benign	0.92	T;.;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.
Polyphen		0.0, 0.0010, 0.0050, 0.0020, 0.040	.;.;.;B;.;.;.;.;.;.;.;.;B;.;B;.;.;B;B;B;B;B;B;B;.;.
Vest4		0.074
MutPred		0.43		Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);
MVP		0.42
MPC		0.027
ClinPred		0.062	T
GERP RS		0.64
Varity_R		0.037
gMVP		0.29

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: rs11004439; hg19: chr10-56423968;