rs1800109

Variant names:

• chr7-117603772-G-A
• rs1800109
• NM_000492.4:c.2898G>A

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.2898G>A​(p.Thr966Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,613,754 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T966T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0085 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (33 hom.)
• Consequence: CFTR NM_000492.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:18
• Conservation: PhyloP100: -3.13
• Publications: 11 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=-0.77).
• BP6: Variant 7-117603772-G-A is Benign according to our data. Variant chr7-117603772-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35853.
• BP7: Synonymous conserved (PhyloP=-3.13 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 8 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.2898G>A	p.Thr966Thr	synonymous	Exon 17 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.2898G>A	p.Thr966Thr	synonymous	Exon 17 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699602.1		c.2898G>A	p.Thr966Thr	synonymous	Exon 17 of 27	ENSP00000514471.1	A0A8V8TNH2
	CFTR	ENST00000889206.1		c.2811G>A	p.Thr937Thr	synonymous	Exon 16 of 26	ENSP00000559265.1

Frequencies

GnomAD3 genomes AF: 0.00855 AC: 1301 AN: 152158 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.0129

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00950

Gnomad ASJ AF: 0.0202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00763

Gnomad OTH AF: 0.00959

GnomAD2 exomes AF: 0.00580 AC: 1457 AN: 251196 AF XY: 0.00542

Gnomad AFR exome AF: 0.0127

Gnomad AMR exome AF: 0.00576

Gnomad ASJ exome AF: 0.0160

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00163

Gnomad NFE exome AF: 0.00714

Gnomad OTH exome AF: 0.00522

GnomAD4 exome AF: 0.00591 AC: 8636 AN: 1461478 Hom.: 33 Cov.: 32 AF XY: 0.00576 AC XY: 4188 AN XY: 727038

African (AFR) AF: 0.0147 AC: 492 AN: 33458

American (AMR) AF: 0.00557 AC: 249 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 406 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.000371 AC: 32 AN: 86254

European-Finnish (FIN) AF: 0.00158 AC: 84 AN: 53266

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5766

European-Non Finnish (NFE) AF: 0.00625 AC: 6949 AN: 1111848

Other (OTH) AF: 0.00666 AC: 402 AN: 60380

GnomAD4 genome AF: 0.00854 AC: 1300 AN: 152276 Hom.: 8 Cov.: 33 AF XY: 0.00770 AC XY: 573 AN XY: 74450

African (AFR) AF: 0.0128 AC: 533 AN: 41558

American (AMR) AF: 0.00948 AC: 145 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0202 AC: 70 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.000848 AC: 9 AN: 10614

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.00763 AC: 519 AN: 68024

Other (OTH) AF: 0.00949 AC: 20 AN: 2108

Alfa AF: 0.00783 Hom.: 1

Bravo AF: 0.00924

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00693

EpiControl AF: 0.00871

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	Cystic fibrosis (6)
-	-	5	not provided (5)
-	-	5	not specified (5)
-	1	2	CFTR-related disorder (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.22
DANN	Benign	0.76
PhyloP100		-3.1
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800109; hg19: chr7-117243826;