chr10-84194816-G-T

Variant names:

• chr10-84194816-G-T
• rs547198427
• NM_033100.4:c.55+1G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_033100.4(CDHR1):​c.55+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000029 in 1,380,678 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CDHR1 NM_033100.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.16

Genes affected

CDHR1 (HGNC:14550): (cadherin related family member 1) This gene belongs to the cadherin superfamily of calcium-dependent cell adhesion molecules. The encoded protein is a photoreceptor-specific cadherin that plays a role in outer segment disc morphogenesis. Mutations in this gene are associated with inherited retinal dystrophies. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.10813954 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.2, offset of -41, new splice context is: ccgGTgggc. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDHR1	NM_033100.4	c.55+1G>T		splice_donor_variant, intron_variant	Intron 1 of 16	ENST00000623527.4	NP_149091.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDHR1	ENST00000623527.4	c.55+1G>T		splice_donor_variant, intron_variant	Intron 1 of 16	1	NM_033100.4	ENSP00000485478.1
CDHR1	ENST00000332904.7	c.55+1G>T		splice_donor_variant, intron_variant	Intron 1 of 16	1		ENSP00000331063.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000290 AC: 4 AN: 1380678 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 681378

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: 0.00000371

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.67	D
GERP RS		3.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: -42
DS_DL_spliceai		1.0		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs547198427; hg19: chr10-85954572;