chr19-3770753-C-CCCCGGG

Position:

• chr19-3770753-C-CCCCGGG

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BS1_Supporting BS2

The ENST00000555633.3(RAX2):​c.422_423insCCCGGG​(p.Pro140_Gly141dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00032 in 1,531,106 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00034 (4 hom.)
• Consequence: RAX2 ENST00000555633.3 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:1
• Conservation: PhyloP100: 1.70

Genes affected

RAX2 (HGNC:18286): (retina and anterior neural fold homeobox 2) This gene encodes a homeodomain-containing protein that plays a role in eye development. Mutation of this gene causes age-related macular degeneration type 6, an eye disorder resulting in accumulations of protein and lipid beneath the retinal pigment epithelium and within the Bruch's membrane. Defects in this gene can also cause cone-rod dystrophy type 11, a disease characterized by the initial degeneration of cone photoreceptor cells and resulting in loss of color vision and visual acuity, followed by the degeneration of rod photoreceptor cells, which progresses to night blindness and the loss of peripheral vision. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in ENST00000555633.3.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000144 (22/152312) while in subpopulation SAS AF= 0.00352 (17/4834). AF 95% confidence interval is 0.00224. There are 0 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAX2	NM_001319074.4	c.422_423insCCCGGG	p.Pro140_Gly141dup	inframe_insertion	3/3	ENST00000555633.3	NP_001306003.2
RAX2	NM_032753.4	c.422_423insCCCGGG	p.Pro140_Gly141dup	inframe_insertion	3/3		NP_116142.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAX2	ENST00000555633.3	c.422_423insCCCGGG	p.Pro140_Gly141dup	inframe_insertion	3/3	1	NM_001319074.4	ENSP00000450456	P1
RAX2	ENST00000555978.5	c.422_423insCCCGGG	p.Pro140_Gly141dup	inframe_insertion	3/3	1		ENSP00000450687	P1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000733 AC: 92 AN: 125538 Hom.: 0 AF XY: 0.000929 AC XY: 64 AN XY: 68876

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00392

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000858

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000339 AC: 468 AN: 1378794 Hom.: 4 Cov.: 31 AF XY: 0.000444 AC XY: 302 AN XY: 680382

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000282

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000284

Gnomad4 SAS exome AF: 0.00433

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000975

Gnomad4 OTH exome AF: 0.000330

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74472

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cone-rod dystrophy 11 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Sep 24, 2020	This variant (reported as, 140P_141Gdup) was previously reported in a patient with cone-rod dystrophy in heterozygous state and also identified in the proband's mother and two siblings with normal vision but possibility of mild CORD could not be excluded in them as mentioned in the article. Functional studies using co-immunoprecipitation analysis suggested proteins with the variant have decreased interaction with Crx and increased transactivation activity [PMID: 15028672]. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 15, 2004	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs549932754; hg19: chr19-3770751;