rs1800095

Variant names:

• chr7-117559655-G-A
• rs1800095
• NM_000492.4:c.1584G>A
• CFTR p.Glu528Glu

Your query was ambiguous. Multiple possible variants found:

• chr7-117559655-G-A
• chr7-117559655-G-C
• chr7-117559655-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_000492.4(CFTR):​c.1584G>A​(p.Glu528Glu) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.0201 in 1,609,992 control chromosomes in the GnomAD database, including 394 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.017 (37 hom., cov: 32)
  • Exomes 𝑓: 0.020 (357 hom.)
• Consequence: CFTR NM_000492.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.9939
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:16 O:3
• Conservation: PhyloP100: 6.38
• Publications: 39 publications found

Genes affected

CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

CFTR-AS1 (HGNC:40144): (CFTR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 7-117559655-G-A is Benign according to our data. Variant chr7-117559655-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43576.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.017 (2580/152136) while in subpopulation AMR AF = 0.0302 (462/15286). AF 95% confidence interval is 0.0279. There are 37 homozygotes in GnomAd4. There are 1239 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. 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
	CFTR	NM_000492.4	MANE Select	c.1584G>A	p.Glu528Glu	splice_region synonymous	Exon 11 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.221+1078C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1584G>A	p.Glu528Glu	splice_region synonymous	Exon 11 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1584G>A	p.Glu528Glu	splice_region synonymous	Exon 11 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1584G>A	p.Glu528Glu	splice_region synonymous	Exon 11 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2581 AN: 152020 Hom.: 37 Cov.: 32

Gnomad AFR AF: 0.00435

Gnomad AMI AF: 0.0308

Gnomad AMR AF: 0.0303

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00332

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0234

Gnomad OTH AF: 0.0192

GnomAD2 exomes AF: 0.0167 AC: 4190 AN: 250582 AF XY: 0.0166

Gnomad AFR exome AF: 0.00462

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0238

Gnomad NFE exome AF: 0.0241

Gnomad OTH exome AF: 0.0203

GnomAD4 exome AF: 0.0204 AC: 29752 AN: 1457856 Hom.: 357 Cov.: 29 AF XY: 0.0200 AC XY: 14522 AN XY: 725568

African (AFR) AF: 0.00315 AC: 105 AN: 33380

American (AMR) AF: 0.0190 AC: 848 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 58 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00316 AC: 272 AN: 86156

European-Finnish (FIN) AF: 0.0239 AC: 1266 AN: 53018

Middle Eastern (MID) AF: 0.00713 AC: 41 AN: 5748

European-Non Finnish (NFE) AF: 0.0236 AC: 26215 AN: 1108884

Other (OTH) AF: 0.0157 AC: 947 AN: 60272

GnomAD4 genome AF: 0.0170 AC: 2580 AN: 152136 Hom.: 37 Cov.: 32 AF XY: 0.0167 AC XY: 1239 AN XY: 74370

African (AFR) AF: 0.00433 AC: 180 AN: 41534

American (AMR) AF: 0.0302 AC: 462 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4820

European-Finnish (FIN) AF: 0.0240 AC: 254 AN: 10578

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0234 AC: 1588 AN: 67954

Other (OTH) AF: 0.0190 AC: 40 AN: 2110

Alfa AF: 0.0197 Hom.: 137

Bravo AF: 0.0165

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.0220

EpiControl AF: 0.0213

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	5	Cystic fibrosis (7)
-	1	5	not provided (6)
-	1	3	CFTR-related disorder (4)
-	-	2	not specified (3)
-	1	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
-	1	-	Congenital bilateral aplasia of vas deferens from CFTR mutation (1)
-	-	1	Hereditary pancreatitis (2)
-	-	-	Pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Benign	0.89
PhyloP100		6.4
Mutation Taster		=12/88	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.98
Splicevardb		3.0
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1800095;

hg19: chr7-117199709;

COSMIC: COSV50089416;

COSMIC: COSV50089416;