Genetic Variant CNGA1:c.225-33C>T (chr4-47949928-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001379270.1(CNGA1):c.225-33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.816 in 1,604,472 control chromosomes in the GnomAD database, including 536,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.85 ( 55480 hom., cov: 33)

Exomes 𝑓: 0.81 ( 481233 hom. )

Consequence

CNGA1
NM_001379270.1 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.142

Publications

15 publications found

Variant links:

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]

CNGA1 links:

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]

NIPAL1 links:

LOC101927157 (HGNC:):

LOC101927157 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 4-47949928-G-A is Benign according to our data. Variant chr4-47949928-G-A is described in ClinVar as Benign. ClinVar VariationId is 1217359.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CNGA1	NM_001379270.1	MANE Select	c.225-33C>T	intron	N/A	NP_001366199.1	P29973
CNGA1	NM_000087.5		c.225-33C>T	intron	N/A	NP_000078.3	P29973
CNGA1	NM_001142564.2		c.225-33C>T	intron	N/A	NP_001136036.2	P29973

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CNGA1	ENST00000514170.7	TSL:5 MANE Select	c.225-33C>T	intron	N/A	ENSP00000426862.3	P29973
CNGA1	ENST00000402813.9	TSL:1	c.225-33C>T	intron	N/A	ENSP00000384264.5	P29973
CNGA1	ENST00000420489.7	TSL:2	c.225-33C>T	intron	N/A	ENSP00000389881.3	P29973

Frequencies

GnomAD3 genomes

AF:

0.851

AC:

129435

AN:

152128

Hom.:

55422

Cov.:

show subpopulations

Gnomad AFR

AF:

0.920

Gnomad AMI

AF:

0.826

Gnomad AMR

AF:

0.871

Gnomad ASJ

AF:

0.694

Gnomad EAS

AF:

0.979

Gnomad SAS

AF:

0.794

Gnomad FIN

AF:

0.880

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.803

Gnomad OTH

AF:

0.826

GnomAD2 exomes

AF:

0.837

AC:

207969

AN:

248476

AF XY:

0.827

show subpopulations

Gnomad AFR exome

AF:

0.925

Gnomad AMR exome

AF:

0.909

Gnomad ASJ exome

AF:

0.687

Gnomad EAS exome

AF:

0.974

Gnomad FIN exome

AF:

0.873

Gnomad NFE exome

AF:

0.801

Gnomad OTH exome

AF:

0.815

GnomAD4 exome

AF:

0.813

AC:

1180078

AN:

1452226

Hom.:

481233

Cov.:

AF XY:

0.810

AC XY:

586017

AN XY:

723136

show subpopulations

African (AFR)

AF:

0.924

AC:

30770

AN:

33318

American (AMR)

AF:

0.902

AC:

40312

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.688

AC:

17913

AN:

26034

East Asian (EAS)

AF:

0.973

AC:

38546

AN:

39632

South Asian (SAS)

AF:

0.790

AC:

67950

AN:

85990

European-Finnish (FIN)

AF:

0.874

AC:

46666

AN:

53384

Middle Eastern (MID)

AF:

0.719

AC:

4125

AN:

5740

European-Non Finnish (NFE)

AF:

0.802

AC:

885023

AN:

1103360

Other (OTH)

AF:

0.812

AC:

48773

AN:

60088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

10253

20505

30758

41010

51263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20622

41244

61866

82488

103110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.851

AC:

129554

AN:

152246

Hom.:

55480

Cov.:

AF XY:

0.852

AC XY:

63439

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.921

AC:

38248

AN:

41550

American (AMR)

AF:

0.871

AC:

13322

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.694

AC:

2409

AN:

3470

East Asian (EAS)

AF:

0.979

AC:

5074

AN:

5184

South Asian (SAS)

AF:

0.793

AC:

3828

AN:

4826

European-Finnish (FIN)

AF:

0.880

AC:

9329

AN:

10602

Middle Eastern (MID)

AF:

0.759

AC:

223

AN:

294

European-Non Finnish (NFE)

AF:

0.803

AC:

54617

AN:

68000

Other (OTH)

AF:

0.829

AC:

1752

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

983

1967

2950

3934

4917

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.820

Hom.:

13104

Bravo

AF:

0.854

Asia WGS

AF:

0.893

AC:

3106

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Retinitis pigmentosa 49 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

1.7

(source)

DANN

Benign

0.22

PhyloP100

0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over