chr6-42179248-C-G

Variant names:

• chr6-42179248-C-G
• rs121434631
• NM_001384910.1:c.451C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001384910.1(GUCA1A):​c.451C>G​(p.Leu151Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. L151F) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GUCA1A NM_001384910.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.77

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-42179248-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.28281975).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GUCA1A	NM_001384910.1	c.451C>G	p.Leu151Val	missense_variant	Exon 4 of 4	ENST00000372958.2	NP_001371839.1
GUCA1ANB-GUCA1A	NM_000409.5	c.451C>G	p.Leu151Val	missense_variant	Exon 6 of 6		NP_000400.2
GUCA1ANB-GUCA1A	NM_001319061.2	c.451C>G	p.Leu151Val	missense_variant	Exon 6 of 6		NP_001305990.1
GUCA1ANB-GUCA1A	NM_001319062.2	c.451C>G	p.Leu151Val	missense_variant	Exon 5 of 5		NP_001305991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GUCA1A	ENST00000372958.2	c.451C>G	p.Leu151Val	missense_variant	Exon 4 of 4	1	NM_001384910.1	ENSP00000362049.1
ENSG00000290147	ENST00000654459.1	c.451C>G	p.Leu151Val	missense_variant	Exon 5 of 5			ENSP00000499539.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250276 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135406

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	.;T;T;T
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.90	D;.;.;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.97	.;L;L;L
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.8	.;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.066	.;T;T;T
Sift4G	Benign	0.078	T;T;T;T
Polyphen		1.0	.;D;D;D
Vest4		0.48
MutPred		0.56		.;Gain of disorder (P = 0.2233);Gain of disorder (P = 0.2233);Gain of disorder (P = 0.2233);
MVP		0.79
MPC		0.88
ClinPred		0.74	D
GERP RS		3.3
Varity_R		0.23
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121434631; hg19: chr6-42146986;