4-47942012-CAAAAAA-CAAAA

Variant names:

• chr4-47942012-CAA-C
• rs10709670
• NM_001379270.1:c.545+27_545+28delTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001379270.1(CNGA1):​c.545+27_545+28delTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0778 in 1,150,820 control chromosomes in the GnomAD database, including 133 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.037 (80 hom., cov: 0)
  • Exomes 𝑓: 0.083 (53 hom.)
• Consequence: CNGA1 NM_001379270.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.526
• Publications: 3 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 4-47942012-CAA-C is Benign according to our data. Variant chr4-47942012-CAA-C is described in ClinVar as Benign. ClinVar VariationId is 1226008.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0368 (4691/127620) while in subpopulation NFE AF = 0.05 (2978/59564). AF 95% confidence interval is 0.0485. There are 80 homozygotes in GnomAd4. There are 2165 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 80 AD,AR gene

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.545+27_545+28delTT		intron	N/A	NP_001366199.1	P29973
	CNGA1	NM_000087.5		c.545+27_545+28delTT		intron	N/A	NP_000078.3	P29973
	CNGA1	NM_001142564.2		c.545+27_545+28delTT		intron	N/A	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.545+27_545+28delTT		intron	N/A	ENSP00000426862.3	P29973
	CNGA1	ENST00000402813.9	TSL:1	c.545+27_545+28delTT		intron	N/A	ENSP00000384264.5	P29973
	CNGA1	ENST00000420489.7	TSL:2	c.545+27_545+28delTT		intron	N/A	ENSP00000389881.3	P29973

Frequencies

GnomAD3 genomes AF: 0.0367 AC: 4687 AN: 127614 Hom.: 80 Cov.: 0

Gnomad AFR AF: 0.0198

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00426

Gnomad SAS AF: 0.0226

Gnomad FIN AF: 0.0600

Gnomad MID AF: 0.0455

Gnomad NFE AF: 0.0500

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.101 AC: 13999 AN: 138906 AF XY: 0.100

Gnomad AFR exome AF: 0.0966

Gnomad AMR exome AF: 0.0953

Gnomad ASJ exome AF: 0.0485

Gnomad EAS exome AF: 0.0804

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.0931

GnomAD4 exome AF: 0.0830 AC: 84892 AN: 1023200 Hom.: 53 AF XY: 0.0815 AC XY: 42469 AN XY: 520794

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

African (AFR) AF: 0.0701 AC: 1566 AN: 22336

American (AMR) AF: 0.0859 AC: 2849 AN: 33184

Ashkenazi Jewish (ASJ) AF: 0.0523 AC: 1118 AN: 21378

East Asian (EAS) AF: 0.0599 AC: 1962 AN: 32780

South Asian (SAS) AF: 0.0539 AC: 3588 AN: 66624

European-Finnish (FIN) AF: 0.0939 AC: 3534 AN: 37620

Middle Eastern (MID) AF: 0.0801 AC: 305 AN: 3806

European-Non Finnish (NFE) AF: 0.0875 AC: 66613 AN: 760916

Other (OTH) AF: 0.0753 AC: 3357 AN: 44556

⚠️ 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 AF: 0.0368 AC: 4691 AN: 127620 Hom.: 80 Cov.: 0 AF XY: 0.0353 AC XY: 2165 AN XY: 61248

African (AFR) AF: 0.0199 AC: 679 AN: 34064

American (AMR) AF: 0.0271 AC: 344 AN: 12686

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 61 AN: 3058

East Asian (EAS) AF: 0.00428 AC: 19 AN: 4444

South Asian (SAS) AF: 0.0225 AC: 89 AN: 3958

European-Finnish (FIN) AF: 0.0600 AC: 426 AN: 7104

Middle Eastern (MID) AF: 0.0458 AC: 11 AN: 240

European-Non Finnish (NFE) AF: 0.0500 AC: 2978 AN: 59564

Other (OTH) AF: 0.0415 AC: 71 AN: 1710

Alfa AF: 0.0496 Hom.: 1208

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs10709670; hg19: chr4-47944029;