rs1800136

Variant names:

• chr7-117667054-G-A
• rs1800136
• NM_000492.4:c.4389G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000492.4(CFTR):​c.4389G>A​(p.Gln1463Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,613,520 control chromosomes in the GnomAD database, including 43,634 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4361 hom., cov: 32)
  • Exomes 𝑓: 0.22 (39273 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 0.00800
• Publications: 57 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 Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Laboratory for Molecular Medicine
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-117667054-G-A is Benign according to our data. Variant chr7-117667054-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.008 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

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.4389G>A	p.Gln1463Gln	synonymous	Exon 27 of 27	NP_000483.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.4389G>A	p.Gln1463Gln	synonymous	Exon 27 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.4383G>A	p.Gln1461Gln	synonymous	Exon 27 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.4302G>A	p.Gln1434Gln	synonymous	Exon 26 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34962 AN: 151946 Hom.: 4352 Cov.: 32

Gnomad AFR AF: 0.243

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.243

Gnomad FIN AF: 0.360

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.235

Gnomad OTH AF: 0.219

GnomAD2 exomes AF: 0.216 AC: 54312 AN: 250926 AF XY: 0.223

Gnomad AFR exome AF: 0.241

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.0183

Gnomad FIN exome AF: 0.352

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.226

GnomAD4 exome AF: 0.225 AC: 328310 AN: 1461456 Hom.: 39273 Cov.: 34 AF XY: 0.226 AC XY: 164504 AN XY: 727058

African (AFR) AF: 0.246 AC: 8250 AN: 33474

American (AMR) AF: 0.128 AC: 5725 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 3947 AN: 26128

East Asian (EAS) AF: 0.0171 AC: 678 AN: 39676

South Asian (SAS) AF: 0.272 AC: 23441 AN: 86256

European-Finnish (FIN) AF: 0.349 AC: 18665 AN: 53414

Middle Eastern (MID) AF: 0.227 AC: 1309 AN: 5766

European-Non Finnish (NFE) AF: 0.228 AC: 253438 AN: 1111658

Other (OTH) AF: 0.213 AC: 12857 AN: 60382

GnomAD4 genome AF: 0.230 AC: 35017 AN: 152064 Hom.: 4361 Cov.: 32 AF XY: 0.234 AC XY: 17397 AN XY: 74326

African (AFR) AF: 0.243 AC: 10087 AN: 41470

American (AMR) AF: 0.173 AC: 2648 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 524 AN: 3470

East Asian (EAS) AF: 0.0184 AC: 95 AN: 5168

South Asian (SAS) AF: 0.242 AC: 1165 AN: 4820

European-Finnish (FIN) AF: 0.360 AC: 3804 AN: 10556

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.235 AC: 15972 AN: 67976

Other (OTH) AF: 0.223 AC: 470 AN: 2112

Alfa AF: 0.225 Hom.: 6880

Bravo AF: 0.212

Asia WGS AF: 0.167 AC: 581 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	7	Cystic fibrosis (7)
-	-	3	CFTR-related disorder (3)
-	-	2	not provided (2)
-	-	1	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.033
DANN	Benign	0.36
PhyloP100		0.0080
Mutation Taster		=99/1	polymorphism (auto)

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: rs1800136; hg19: chr7-117307108; COSMIC: COSV50049554;