chr4-47937535-G-A

Variant names:

• chr4-47937535-G-A
• rs62625014
• NM_001379270.1:c.947C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 14P and 2B. PS3 PM1 PP5_Very_Strong BP4 BS2_Supporting

The NM_001379270.1(CNGA1):​c.947C>T​(p.Ser316Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,614,178 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001572159: Based on this evidence we have classified this variant as Likely Pathogenic. PS3; SCV000915088: Dryja et al. (1995) investigated channel function and found the p.Ser389Phe variant was similar to wild type for channel current and open times of the channel, however, the location was found to be intracellular, whereas wild type CNGA1 protein was located at the cell membrane. PMID:7715615; SCV000966829: "In vitro functional studies provide some evidence that the p.Ser320Phe variant may impact protein function (Dryja 1995)."; SCV004241232: The most pronounced variant effect results in <10% of frequencies of detecting functional cGMP-activated channel in HEK293 cells and the variant CNGA1 was predominantly retained inside the cell instead of being targeted to the plasma membrane (Dryja_1995). PMID:7479749; SCV001224360: Experimental studies have shown that this missense change affects CNGA1 function (PMID:7479749).; SCV005344761: Functional studies using protein expression in cell culture found that the p.Ser320Phe substitution causes the protein to mislocalize within the cell (Dryja et al. 1995. PubMed ID: 7479749).". Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S316C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (2 hom.)
• Consequence: CNGA1 NM_001379270.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:22
• Conservation: PhyloP100: 9.54
• Publications: 19 publications found

Genes affected

CNGA1 (HGNC:2148): (cyclic nucleotide gated channel subunit alpha 1) The protein encoded by this gene is involved in phototransduction. Along with another protein, the encoded protein forms a cGMP-gated cation channel in the plasma membrane, allowing depolarization of rod photoreceptors. This represents the last step in the phototransduction pathway. Defects in this gene are a cause of retinitis pigmentosa autosomal recessive (ARRP) disease. Multiple transcript variants have been found for this gene. [provided by RefSeq, Oct 2019]

NIPAL1 (HGNC:27194): (NIPA like domain containing 1) Predicted to enable magnesium ion transmembrane transporter activity. Predicted to be involved in magnesium ion transport. Predicted to be integral component of membrane. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

LOC101927157 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001572159: Based on this evidence we have classified this variant as Likely Pathogenic. PS3; SCV000915088: Dryja et al. (1995) investigated channel function and found the p.Ser389Phe variant was similar to wild type for channel current and open times of the channel, however, the location was found to be intracellular, whereas wild type CNGA1 protein was located at the cell membrane. PMID:7715615; SCV000966829: "In vitro functional studies provide some evidence that the p.Ser320Phe variant may impact protein function (Dryja 1995)."; SCV004241232: The most pronounced variant effect results in <10% of frequencies of detecting functional cGMP-activated channel in HEK293 cells and the variant CNGA1 was predominantly retained inside the cell instead of being targeted to the plasma membrane (Dryja_1995). PMID: 7479749; SCV001224360: Experimental studies have shown that this missense change affects CNGA1 function (PMID: 7479749).; SCV005344761: Functional studies using protein expression in cell culture found that the p.Ser320Phe substitution causes the protein to mislocalize within the cell (Dryja et al. 1995. PubMed ID: 7479749).
• PM1: In a region_of_interest Ion conduction pathway (size 108) in uniprot entity CNGA1_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_001379270.1
• PP5: Variant 4-47937535-G-A is Pathogenic according to our data. Variant chr4-47937535-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 16932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.25471663). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001379270.1. 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
	CNGA1	NM_001379270.1	MANE Select	c.947C>T	p.Ser316Phe	missense	Exon 11 of 11	NP_001366199.1	P29973
	CNGA1	NM_000087.5		c.947C>T	p.Ser316Phe	missense	Exon 11 of 11	NP_000078.3	P29973
	CNGA1	NM_001142564.2		c.947C>T	p.Ser316Phe	missense	Exon 10 of 10	NP_001136036.2	P29973

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CNGA1	ENST00000514170.7	TSL:5 MANE Select	c.947C>T	p.Ser316Phe	missense	Exon 11 of 11	ENSP00000426862.3	P29973
	CNGA1	ENST00000402813.9	TSL:1	c.947C>T	p.Ser316Phe	missense	Exon 10 of 10	ENSP00000384264.5	P29973
	CNGA1	ENST00000420489.7	TSL:2	c.947C>T	p.Ser316Phe	missense	Exon 11 of 11	ENSP00000389881.3	P29973

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 171 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00220

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00110 AC: 274 AN: 249220 AF XY: 0.00115

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000510

Gnomad NFE exome AF: 0.00195

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00173 AC: 2528 AN: 1461838 Hom.: 2 Cov.: 32 AF XY: 0.00169 AC XY: 1232 AN XY: 727216

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.000591 AC: 51 AN: 86250

European-Finnish (FIN) AF: 0.000599 AC: 32 AN: 53406

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00211 AC: 2350 AN: 1111994

Other (OTH) AF: 0.00106 AC: 64 AN: 60394

GnomAD4 genome AF: 0.00112 AC: 171 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.00101 AC XY: 75 AN XY: 74498

African (AFR) AF: 0.000265 AC: 11 AN: 41552

American (AMR) AF: 0.000131 AC: 2 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4834

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00220 AC: 150 AN: 68042

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00168 Hom.: 1

Bravo AF: 0.00104

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000267 AC: 1

ESP6500EA AF: 0.00158 AC: 13

ExAC AF: 0.00103 AC: 124

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00178

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	not provided (6)
5	-	-	Retinitis pigmentosa (5)
5	-	-	Retinitis pigmentosa 49 (5)
2	-	-	Retinal dystrophy (2)
1	-	-	CNGA1-related disorder (1)
1	-	-	Cone-rod dystrophy (1)
1	-	-	Macular dystrophy (1)
1	-	-	See cases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.49
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.25	T
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Benign	1.8	L
PhyloP100		9.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.82
Sift	Benign	0.048	D
Sift4G	Uncertain	0.054	T
Polyphen		0.15	B
Vest4		0.92
MVP		0.97
MPC		0.55
ClinPred		0.056	T
GERP RS		4.8
Varity_R		0.70
gMVP		0.86
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs62625014; hg19: chr4-47939552;