rs61748445

Variant names:

• chr19-47839539-G-A
• rs61748445
• NM_000554.6:c.472G>A

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.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. 12/21 in silico tools predict 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:11 O:1
• Conservation: PhyloP100: 4.24
• Publications: 12 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: ClinGen, 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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 (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 Benign/Likely_benign. ClinVar VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRX	NM_000554.6	MANE Select	c.472G>A	p.Ala158Thr	missense	Exon 4 of 4	NP_000545.1	O43186

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRX	ENST00000221996.12	TSL:2 MANE Select	c.472G>A	p.Ala158Thr	missense	Exon 4 of 4	ENSP00000221996.5	O43186
	CRX	ENST00000613299.1	TSL:3	c.*194G>A		3_prime_UTR	Exon 3 of 3	ENSP00000478106.1	A0A087WTS9

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

GnomAD2 exomes AF: 0.00689 AC: 1720 AN: 249576 AF XY: 0.00499

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 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

African (AFR) AF: 0.0902 AC: 3021 AN: 33476

American (AMR) AF: 0.00620 AC: 277 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00261 AC: 68 AN: 26066

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86214

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53324

Middle Eastern (MID) AF: 0.00503 AC: 29 AN: 5760

European-Non Finnish (NFE) AF: 0.000242 AC: 269 AN: 1111682

Other (OTH) AF: 0.00583 AC: 352 AN: 60352

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

African (AFR) AF: 0.0817 AC: 3391 AN: 41486

American (AMR) AF: 0.0110 AC: 168 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 67972

Other (OTH) AF: 0.0166 AC: 35 AN: 2110

Alfa AF: 0.0115 Hom.: 40

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	not specified (2)
-	-	1	Cone-rod dystrophy 2 (1)
-	-	1	Leber congenital amaurosis 7 (1)
-	-	1	Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 (1)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa (1)
-	-	1	Retinitis pigmentosa;C3151192:Leber congenital amaurosis 7;C3489532:Cone-rod dystrophy 2 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.27
Sift	Benign	0.18	T
Sift4G	Benign	0.21	T
Polyphen		0.012	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
Mutation Taster		=88/12	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: rs61748445; hg19: chr19-48342796; COSMIC: COSV55758113; COSMIC: COSV55758113;