rs104893968

Variant names:

• chr6-42173762-C-A
• rs104893968
• NM_001384910.1:c.149C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-42173762-C-A
• chr6-42173762-C-G
• chr6-42173762-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1 PM2 PP2 BP4_Moderate

The NM_001384910.1(GUCA1A):​c.149C>A​(p.Pro50Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P50L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: GUCA1A NM_001384910.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.64
• Publications: 0 publications found

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]

GUCA1ANB-GUCA1A (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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a chain Guanylyl cyclase-activating protein 1 (size 199) in uniprot entity GUC1A_HUMAN there are 33 pathogenic changes around while only 8 benign (80%) in NM_001384910.1
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 21 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Trascript score misZ: 0.22619 (below the threshold of 3.09). GenCC associations: The gene is linked to cone dystrophy 3, cone-rod dystrophy 14, hereditary macular dystrophy, cone dystrophy, central areolar choroidal dystrophy, cone-rod dystrophy.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2630647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCA1A	NM_001384910.1	c.149C>A	p.Pro50Gln	missense_variant	Exon 1 of 4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_000409.5	c.149C>A	p.Pro50Gln	missense_variant	Exon 3 of 6		NP_000400.2
GUCA1ANB-GUCA1A	NM_001319061.2	c.149C>A	p.Pro50Gln	missense_variant	Exon 3 of 6		NP_001305990.1
GUCA1ANB-GUCA1A	NM_001319062.2	c.149C>A	p.Pro50Gln	missense_variant	Exon 2 of 5		NP_001305991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2	c.149C>A	p.Pro50Gln	missense_variant	Exon 1 of 4	1	NM_001384910.1	ENSP00000362049.1
GUCA1ANB-GUCA1A	ENST00000654459.1	c.149C>A	p.Pro50Gln	missense_variant	Exon 2 of 5			ENSP00000499539.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	0.000052	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.13	.;.;T;T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.71	.;T;.;.;T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.26	T;T;T;T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	0.74	.;.;N;N;N
PhyloP100		2.6
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.77	N;.;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.56	T;.;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T
Polyphen		0.97	.;.;D;D;D
Vest4		0.51, 0.51, 0.54, 0.53
MutPred		0.44		Loss of glycosylation at P50 (P = 0.032);.;Loss of glycosylation at P50 (P = 0.032);Loss of glycosylation at P50 (P = 0.032);Loss of glycosylation at P50 (P = 0.032);
MVP		0.86
MPC		0.46
ClinPred		0.81	D
GERP RS		5.8
PromoterAI		0.0031	Neutral
Varity_R		0.18
gMVP		0.47
Mutation Taster		=74/26	polymorphism

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: rs104893968; hg19: chr6-42141500;