rs1800094

Variant names:

• chr7-117559652-A-G
• rs1800094
• NM_000492.4:c.1581A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000492.4(CFTR):​c.1581A>G​(p.Glu527Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000843 in 1,611,220 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (6 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.31
• Publications: 7 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 7-117559652-A-G is Benign according to our data. Variant chr7-117559652-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00444 (676/152284) while in subpopulation AFR AF = 0.0157 (652/41570). AF 95% confidence interval is 0.0147. There are 6 homozygotes in GnomAd4. There are 315 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.1581A>G	p.Glu527Glu	synonymous	Exon 11 of 27	NP_000483.3
	CFTR-AS1	NR_149084.1		n.221+1081T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1581A>G	p.Glu527Glu	synonymous	Exon 11 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.1581A>G	p.Glu527Glu	synonymous	Exon 11 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.1581A>G	p.Glu527Glu	synonymous	Exon 11 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00444 AC: 676 AN: 152166 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00118 AC: 296 AN: 250744 AF XY: 0.000907

Gnomad AFR exome AF: 0.0167

Gnomad AMR exome AF: 0.000550

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000467 AC: 682 AN: 1458936 Hom.: 6 Cov.: 30 AF XY: 0.000402 AC XY: 292 AN XY: 726024

African (AFR) AF: 0.0176 AC: 588 AN: 33404

American (AMR) AF: 0.000582 AC: 26 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53046

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109852

Other (OTH) AF: 0.000945 AC: 57 AN: 60292

GnomAD4 genome AF: 0.00444 AC: 676 AN: 152284 Hom.: 6 Cov.: 32 AF XY: 0.00423 AC XY: 315 AN XY: 74462

African (AFR) AF: 0.0157 AC: 652 AN: 41570

American (AMR) AF: 0.00105 AC: 16 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68000

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00163 Hom.: 1

Bravo AF: 0.00514

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Cystic fibrosis (3)
-	-	3	not provided (3)
-	-	2	CFTR-related disorder (2)
-	-	2	not specified (2)
-	-	1	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	8.8
DANN	Benign	0.83
PhyloP100		1.3
Mutation Taster		=100/0	polymorphism

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: rs1800094; hg19: chr7-117199706;