rs61748445

chr19-47839539-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000554.6(CRX):c.472G>A(p.Ala158Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00475 in 1,613,370 control chromosomes in the GnomAD database, including 295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (151 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (144 hom.)
• Consequence: CRX NM_000554.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 4.24

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a chain Cone-rod homeobox protein (size 298) in uniprot entity CRX_HUMAN there are 56 pathogenic changes around while only 17 benign (77%) in NM_000554.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023398101).
• BP6: Variant 19-47839539-G-A is Benign according to our data. Variant chr19-47839539-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 99608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0794 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRX	NM_000554.6	c.472G>A	p.Ala158Thr	missense_variant	4/4	ENST00000221996.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRX	ENST00000221996.12	c.472G>A	p.Ala158Thr	missense_variant	4/4	2	NM_000554.6	P1
CRX	ENST00000613299.1	c.*194G>A		3_prime_UTR_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0239 AC: 3628 AN: 152012 Hom.: 150 Cov.: 31

Gnomad AFR AF: 0.0818

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0110

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0168

GnomAD3 exomes AF: 0.00689 AC: 1720 AN: 249576 Hom.: 68 AF XY: 0.00499 AC XY: 674 AN XY: 135118

Gnomad AFR exome AF: 0.0901

Gnomad AMR exome AF: 0.00542

Gnomad ASJ exome AF: 0.00231

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000311

Gnomad OTH exome AF: 0.00477

GnomAD4 exome AF: 0.00276 AC: 4033 AN: 1461240 Hom.: 144 Cov.: 31 AF XY: 0.00241 AC XY: 1751 AN XY: 726892

Gnomad4 AFR exome AF: 0.0902

Gnomad4 AMR exome AF: 0.00620

Gnomad4 ASJ exome AF: 0.00261

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000563

Gnomad4 NFE exome AF: 0.000242

Gnomad4 OTH exome AF: 0.00583

GnomAD4 genome AF: 0.0239 AC: 3636 AN: 152130 Hom.: 151 Cov.: 31 AF XY: 0.0233 AC XY: 1732 AN XY: 74384

Gnomad4 AFR AF: 0.0817

Gnomad4 AMR AF: 0.0110

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0113 Hom.: 32

Bravo AF: 0.0280

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0908 AC: 400

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00821 AC: 996

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 13, 2022	- -
not provided, no classification provided	literature only	Retina International	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 22, 2019	This variant is associated with the following publications: (PMID: 10766140, 20981092) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2014	- -

Retinitis pigmentosa;C3151192:Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 09, 2021

- -

Cone-rod dystrophy 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

Leber congenital amaurosis 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Retinitis pigmentosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.66	D
MetaRNN	Benign	0.0023	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M;M
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.69	N;N
REVEL	Benign	0.27
Sift	Benign	0.18	T;T
Sift4G	Benign	0.21	T;T
Polyphen		0.012	B;B
Vest4		0.40
MVP		0.72
MPC		0.27
ClinPred		0.011	T
GERP RS		2.0
Varity_R		0.058
gMVP		0.55

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: rs61748445; hg19: chr19-48342796; COSMIC: COSV55758113; COSMIC: COSV55758113;