7-117595001-T-G

Position:

• chr7-117595001-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000492.4(CFTR):​c.2562T>G​(p.Thr854=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 1,611,676 control chromosomes in the GnomAD database, including 101,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (15267 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86541 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: 0.278

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-117595001-T-G is Benign according to our data. Variant chr7-117595001-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 43577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-117595001-T-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.278 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.627 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2562T>G	p.Thr854=	synonymous_variant	15/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2562T>G	p.Thr854=	synonymous_variant	15/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64588 AN: 151756 Hom.: 15229 Cov.: 32

Gnomad AFR AF: 0.634

Gnomad AMI AF: 0.220

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.417

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.429

Gnomad MID AF: 0.237

Gnomad NFE AF: 0.321

Gnomad OTH AF: 0.370

GnomAD3 exomes AF: 0.383 AC: 96181 AN: 251152 Hom.: 19751 AF XY: 0.374 AC XY: 50715 AN XY: 135762

Gnomad AFR exome AF: 0.646

Gnomad AMR exome AF: 0.466

Gnomad ASJ exome AF: 0.180

Gnomad EAS exome AF: 0.425

Gnomad SAS exome AF: 0.404

Gnomad FIN exome AF: 0.418

Gnomad NFE exome AF: 0.320

Gnomad OTH exome AF: 0.354

GnomAD4 exome AF: 0.337 AC: 491244 AN: 1459802 Hom.: 86541 Cov.: 32 AF XY: 0.336 AC XY: 244394 AN XY: 726342

Gnomad4 AFR exome AF: 0.651

Gnomad4 AMR exome AF: 0.457

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.407

Gnomad4 SAS exome AF: 0.399

Gnomad4 FIN exome AF: 0.415

Gnomad4 NFE exome AF: 0.315

Gnomad4 OTH exome AF: 0.341

GnomAD4 genome AF: 0.426 AC: 64673 AN: 151874 Hom.: 15267 Cov.: 32 AF XY: 0.429 AC XY: 31828 AN XY: 74216

Gnomad4 AFR AF: 0.634

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.417

Gnomad4 SAS AF: 0.418

Gnomad4 FIN AF: 0.429

Gnomad4 NFE AF: 0.321

Gnomad4 OTH AF: 0.371

Alfa AF: 0.321 Hom.: 6097

Bravo AF: 0.433

Asia WGS AF: 0.466 AC: 1618 AN: 3468

EpiCase AF: 0.296

EpiControl AF: 0.290

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 19, 2018	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 20, 2011	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Cystic fibrosis Benign:5

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 19, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, no assertion criteria provided	clinical testing	Payam Genetics Center, General Welfare Department of North Khorasan Province	Mar 01, 2023	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	the variant does not result in CFTR-RD neither -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

CFTR-related disorder Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 28, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Hereditary pancreatitis Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Dec 09, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.7
DANN	Benign	0.35

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

Publications

LitVar

Other links and lift over

dbSNP: rs1042077; hg19: chr7-117235055; COSMIC: COSV50040915;