7-117595001-T-G

Variant names:

• chr7-117595001-T-G
• rs1042077
• NM_000492.4:c.2562T>G

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.2562T>G​(p.Thr854Thr) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T854T) has been classified 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
• Publications: 85 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=-0.82).
• BP6: Variant 7-117595001-T-G is Benign according to our data. Variant chr7-117595001-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 43577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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.2562T>G	p.Thr854Thr	synonymous	Exon 15 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.2562T>G	p.Thr854Thr	synonymous	Exon 15 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.2562T>G	p.Thr854Thr	synonymous	Exon 15 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.2475T>G	p.Thr825Thr	synonymous	Exon 14 of 26	ENSP00000559265.1

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

GnomAD2 exomes AF: 0.383 AC: 96181 AN: 251152 AF XY: 0.374

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 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

African (AFR) AF: 0.651 AC: 21758 AN: 33428

American (AMR) AF: 0.457 AC: 20403 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4687 AN: 26100

East Asian (EAS) AF: 0.407 AC: 16087 AN: 39522

South Asian (SAS) AF: 0.399 AC: 34398 AN: 86198

European-Finnish (FIN) AF: 0.415 AC: 22123 AN: 53360

Middle Eastern (MID) AF: 0.275 AC: 1558 AN: 5670

European-Non Finnish (NFE) AF: 0.315 AC: 349674 AN: 1110536

Other (OTH) AF: 0.341 AC: 20556 AN: 60302

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

African (AFR) AF: 0.634 AC: 26239 AN: 41416

American (AMR) AF: 0.414 AC: 6317 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 613 AN: 3470

East Asian (EAS) AF: 0.417 AC: 2157 AN: 5170

South Asian (SAS) AF: 0.418 AC: 2015 AN: 4818

European-Finnish (FIN) AF: 0.429 AC: 4503 AN: 10508

Middle Eastern (MID) AF: 0.231 AC: 68 AN: 294

European-Non Finnish (NFE) AF: 0.321 AC: 21779 AN: 67918

Other (OTH) AF: 0.371 AC: 783 AN: 2108

Alfa AF: 0.322 Hom.: 6661

Bravo AF: 0.433

Asia WGS AF: 0.466 AC: 1618 AN: 3468

EpiCase AF: 0.296

EpiControl AF: 0.290

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	Cystic fibrosis (5)
-	-	2	CFTR-related disorder (2)
-	-	2	not provided (2)
-	-	1	Hereditary pancreatitis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.7
DANN	Benign	0.35
PhyloP100		0.28
Mutation Taster		=98/2	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: rs1042077; hg19: chr7-117235055; COSMIC: COSV50040915;