rs62128766

Variant names:

• chr19-47834555-C-T
• rs62128766
• NM_000554.6:c.100+12C>T

Variant summary

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

The NM_000554.6(CRX):​c.100+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 1,608,494 control chromosomes in the GnomAD database, including 24,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1752 hom., cov: 31)
  • Exomes 𝑓: 0.17 (22896 hom.)
• Consequence: CRX NM_000554.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: -0.233
• Publications: 7 publications found

Genes affected

CRX (HGNC:2383): (cone-rod homeobox) The protein encoded by this gene is a photoreceptor-specific transcription factor which plays a role in the differentiation of photoreceptor cells. This homeodomain protein is necessary for the maintenance of normal cone and rod function. Mutations in this gene are associated with photoreceptor degeneration, Leber congenital amaurosis type III and the autosomal dominant cone-rod dystrophy 2. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some variants has not been determined. [provided by RefSeq, Jul 2008]

CRX Gene-Disease associations (from GenCC):

• cone-rod dystrophy 2

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary macular dystrophy

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Leber congenital amaurosis 7

  Inheritance: AD, AR, SD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• cone-rod dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-47834555-C-T is Benign according to our data. Variant chr19-47834555-C-T is described in ClinVar as Benign. ClinVar VariationId is 99592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000554.6. 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
	CRX	NM_000554.6	MANE Select	c.100+12C>T		intron	N/A	NP_000545.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRX	ENST00000221996.12	TSL:2 MANE Select	c.100+12C>T		intron	N/A	ENSP00000221996.5
	CRX	ENST00000556527.1	TSL:1	n.78-1688C>T		intron	N/A
	CRX	ENST00000566686.5	TSL:5	c.100+12C>T		intron	N/A	ENSP00000457808.2

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21322 AN: 151962 Hom.: 1752 Cov.: 31

Gnomad AFR AF: 0.0844

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.159

Gnomad FIN AF: 0.194

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.143

GnomAD2 exomes AF: 0.143 AC: 35773 AN: 250070 AF XY: 0.149

Gnomad AFR exome AF: 0.0804

Gnomad AMR exome AF: 0.0735

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.00125

Gnomad FIN exome AF: 0.190

Gnomad NFE exome AF: 0.178

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.173 AC: 251642 AN: 1456414 Hom.: 22896 Cov.: 30 AF XY: 0.173 AC XY: 125555 AN XY: 724796

African (AFR) AF: 0.0817 AC: 2728 AN: 33376

American (AMR) AF: 0.0765 AC: 3414 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 4563 AN: 26110

East Asian (EAS) AF: 0.000655 AC: 26 AN: 39668

South Asian (SAS) AF: 0.171 AC: 14738 AN: 86094

European-Finnish (FIN) AF: 0.185 AC: 9877 AN: 53364

Middle Eastern (MID) AF: 0.176 AC: 1013 AN: 5760

European-Non Finnish (NFE) AF: 0.186 AC: 205457 AN: 1107202

Other (OTH) AF: 0.163 AC: 9826 AN: 60188

GnomAD4 genome AF: 0.140 AC: 21327 AN: 152080 Hom.: 1752 Cov.: 31 AF XY: 0.140 AC XY: 10373 AN XY: 74342

African (AFR) AF: 0.0844 AC: 3504 AN: 41512

American (AMR) AF: 0.109 AC: 1662 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 612 AN: 3464

East Asian (EAS) AF: 0.00175 AC: 9 AN: 5148

South Asian (SAS) AF: 0.160 AC: 773 AN: 4822

European-Finnish (FIN) AF: 0.194 AC: 2050 AN: 10576

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.180 AC: 12224 AN: 67972

Other (OTH) AF: 0.141 AC: 299 AN: 2114

Alfa AF: 0.162 Hom.: 607

Bravo AF: 0.131

Asia WGS AF: 0.0680 AC: 239 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	Cone-rod dystrophy 2 (1)
-	-	1	Leber congenital amaurosis 7 (1)
-	-	1	Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 (1)
-	-	1	not specified (1)
-	-	1	Retinitis pigmentosa (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.30
PhyloP100		-0.23
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: rs62128766; hg19: chr19-48337812;