rs121908760

chr7-117592292-C-Gchr7-117592292-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_000492.4(CFTR):c.2125C>G(p.Arg709Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,754 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R709Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.50

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-117592293-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53441.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.2125C>G	p.Arg709Gly	missense_variant	14/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.2125C>G	p.Arg709Gly	missense_variant	14/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461754 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727164

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 13, 2021

Variant summary: CFTR c.2125C>G (p.Arg709Gly) results in a non-conservative amino acid change located in the regulator domain (IPR025837) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250834 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2125C>G in individuals affected with Chronic Pancreatitis Risk and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Cystic fibrosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 19, 2021

The p.R709G variant (also known as c.2125C>G), located in coding exon 14 of the CFTR gene, results from a C to G substitution at nucleotide position 2125. The arginine at codon 709 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;D;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Uncertain	2.3	M;.;.;.
MutationTaster	Benign	0.97	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N;.;N;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.013	D;.;D;.
Sift4G	Pathogenic	0.0010	D;.;D;.
Polyphen		0.69	P;.;.;.
Vest4		0.68
MutPred		0.54		Loss of MoRF binding (P = 0.0155);.;.;.;
MVP		0.99
MPC		0.0048
ClinPred		0.97	D
GERP RS		-0.49
Varity_R		0.42
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-117232346;