7-117666937-C-T

Variant names:

• chr7-117666937-C-T
• rs1800135
• NM_000492.4:c.4272C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_000492.4(CFTR):​c.4272C>T​(p.Tyr1424Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,614,018 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (60 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:20
• Conservation: PhyloP100: -2.86
• Publications: 12 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 7-117666937-C-T is Benign according to our data. Variant chr7-117666937-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 93156.
• BP7: Synonymous conserved (PhyloP=-2.86 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 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.4272C>T	p.Tyr1424Tyr	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.4272C>T	p.Tyr1424Tyr	synonymous	Exon 27 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.4266C>T	p.Tyr1422Tyr	synonymous	Exon 27 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.4185C>T	p.Tyr1395Tyr	synonymous	Exon 26 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00664 AC: 1011 AN: 152160 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.00806

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00433

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00902

Gnomad OTH AF: 0.00575

GnomAD2 exomes AF: 0.00667 AC: 1672 AN: 250688 AF XY: 0.00685

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00539

Gnomad ASJ exome AF: 0.0254

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00365

Gnomad NFE exome AF: 0.00868

Gnomad OTH exome AF: 0.00832

GnomAD4 exome AF: 0.00762 AC: 11137 AN: 1461740 Hom.: 60 Cov.: 31 AF XY: 0.00757 AC XY: 5507 AN XY: 727172

African (AFR) AF: 0.00111 AC: 37 AN: 33474

American (AMR) AF: 0.00584 AC: 261 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0263 AC: 687 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00329 AC: 284 AN: 86258

European-Finnish (FIN) AF: 0.00328 AC: 175 AN: 53418

Middle Eastern (MID) AF: 0.00711 AC: 41 AN: 5766

European-Non Finnish (NFE) AF: 0.00827 AC: 9198 AN: 1111920

Other (OTH) AF: 0.00752 AC: 454 AN: 60392

GnomAD4 genome AF: 0.00664 AC: 1011 AN: 152278 Hom.: 7 Cov.: 32 AF XY: 0.00653 AC XY: 486 AN XY: 74446

African (AFR) AF: 0.00147 AC: 61 AN: 41558

American (AMR) AF: 0.00805 AC: 123 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4826

European-Finnish (FIN) AF: 0.00433 AC: 46 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00902 AC: 614 AN: 68034

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00910 Hom.: 7

Bravo AF: 0.00736

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0115

EpiControl AF: 0.0104

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	Cystic fibrosis (7)
-	-	6	not specified (6)
-	-	4	not provided (4)
-	1	2	CFTR-related disorder (3)
-	-	1	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.63
DANN	Benign	0.35
PhyloP100		-2.9
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1800135; hg19: chr7-117306991; COSMIC: COSV105835521;