7-117590404-C-T

Variant names:

• chr7-117590404-C-T
• rs55928397
• NM_000492.4:c.1731C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP7

The NM_000492.4(CFTR):​c.1731C>T​(p.Tyr577Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,603,002 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:2
• Conservation: PhyloP100: -0.0580
• Publications: 8 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP7: Synonymous conserved (PhyloP=-0.058 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1731C>T	p.Tyr577Tyr	synonymous	Exon 13 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1731C>T	p.Tyr577Tyr	synonymous	Exon 13 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1731C>T	p.Tyr577Tyr	synonymous	Exon 13 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.1641C>T	p.Tyr547Tyr	synonymous	Exon 12 of 26	ENSP00000389119.1

Frequencies

GnomAD3 genomes AF: 0.0000856 AC: 13 AN: 151926 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000945

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000208 AC: 52 AN: 250308 AF XY: 0.000236

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000371

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000242 AC: 351 AN: 1450958 Hom.: 0 Cov.: 30 AF XY: 0.000238 AC XY: 172 AN XY: 721710

African (AFR) AF: 0.0000301 AC: 1 AN: 33238

American (AMR) AF: 0.000315 AC: 14 AN: 44384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25618

East Asian (EAS) AF: 0.00 AC: 0 AN: 39354

South Asian (SAS) AF: 0.00 AC: 0 AN: 86110

European-Finnish (FIN) AF: 0.0000951 AC: 5 AN: 52582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.000289 AC: 319 AN: 1104288

Other (OTH) AF: 0.000201 AC: 12 AN: 59690

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152044 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74320

African (AFR) AF: 0.0000241 AC: 1 AN: 41514

American (AMR) AF: 0.000131 AC: 2 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.0000945 AC: 1 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000133 AC: 9 AN: 67886

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000269 Hom.: 0

Bravo AF: 0.000121

EpiCase AF: 0.000164

EpiControl AF: 0.000237

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	2	Cystic fibrosis (5)
-	5	-	not provided (5)
-	1	-	Bronchiectasis with or without elevated sweat chloride 1 (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	2.4
DANN	Benign	0.67
PhyloP100		-0.058
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs55928397; hg19: chr7-117230458;