chr6-42179364-C-T

Position:

• chr6-42179364-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001384910.1(GUCA1A):​c.567C>T​(p.Asp189Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00249 in 1,611,224 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (24 hom.)
• Consequence: GUCA1A NM_001384910.1 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.98

Genes affected

GUCA1A (HGNC:4678): (guanylate cyclase activator 1A) This gene encodes an enzyme that plays a role in the recovery of retinal photoreceptors from photobleaching. This enzyme promotes the activity of retinal guanylyl cyclase-1 (GC1) at low calcium concentrations and inhibits GC1 at high calcium concentrations. Mutations in this gene can cause cone dystrophy 3 and code-rod dystrophy 14. provided by RefSeq, Jul 2020]

ENSG00000290147 (HGNC:56129): (GUCA1ANB-GUCA1A readthrough) This locus represents naturally occurring readthrough transcription between the neighboring GUCA1ANB (GUCA1A neighbor) and GUCA1A (guanylate cyclase activator 1A) genes on chromosome 6. The readthrough transcript encodes the same protein as GUCA1A. [provided by RefSeq, Jul 2020]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-42179364-C-T is Benign according to our data. Variant chr6-42179364-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 256032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-42179364-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.98 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1812/152304) while in subpopulation AFR AF= 0.0394 (1639/41552). AF 95% confidence interval is 0.0379. There are 31 homozygotes in gnomad4. There are 839 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1812 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GUCA1A	NM_001384910.1	c.567C>T	p.Asp189Asp	synonymous_variant	4/4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_000409.5	c.567C>T	p.Asp189Asp	synonymous_variant	6/6		NP_000400.2
GUCA1ANB-GUCA1A	NM_001319061.2	c.567C>T	p.Asp189Asp	synonymous_variant	6/6		NP_001305990.1
GUCA1ANB-GUCA1A	NM_001319062.2	c.567C>T	p.Asp189Asp	synonymous_variant	5/5		NP_001305991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2	c.567C>T	p.Asp189Asp	synonymous_variant	4/4	1	NM_001384910.1	ENSP00000362049.1
ENSG00000290147	ENST00000654459.1	c.567C>T	p.Asp189Asp	synonymous_variant	5/5			ENSP00000499539.1

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1806 AN: 152186 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.0394

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00700

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.00337 AC: 827 AN: 245350 Hom.: 11 AF XY: 0.00257 AC XY: 342 AN XY: 133116

Gnomad AFR exome AF: 0.0389

Gnomad AMR exome AF: 0.00364

Gnomad ASJ exome AF: 0.000305

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000580

Gnomad OTH exome AF: 0.00449

GnomAD4 exome AF: 0.00150 AC: 2195 AN: 1458920 Hom.: 24 Cov.: 31 AF XY: 0.00134 AC XY: 969 AN XY: 725416

Gnomad4 AFR exome AF: 0.0391

Gnomad4 AMR exome AF: 0.00390

Gnomad4 ASJ exome AF: 0.000615

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000931

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000362

Gnomad4 OTH exome AF: 0.00397

GnomAD4 genome AF: 0.0119 AC: 1812 AN: 152304 Hom.: 31 Cov.: 32 AF XY: 0.0113 AC XY: 839 AN XY: 74474

Gnomad4 AFR AF: 0.0394

Gnomad4 AMR AF: 0.00699

Gnomad4 ASJ AF: 0.00115

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: 0.00576 Hom.: 8

Bravo AF: 0.0132

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 2021	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Cone dystrophy 3 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, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cone dystrophy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.24
DANN	Benign	0.61

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: rs34925828; hg19: chr6-42147102;