NM_000492.4:c.202A>G

Variant names:

• chr7-117509071-A-G
• rs397508332
• NM_000492.4:c.202A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 3P and 3B. PM1 PP2 BP4_Moderate BS2_Supporting

The NM_000492.4(CFTR):​c.202A>G​(p.Lys68Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000899 in 1,612,996 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K68N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000092 (2 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1 O:1
• Conservation: PhyloP100: 5.45
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 21 uncertain in NM_000492.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1906983).
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.202A>G	p.Lys68Glu	missense	Exon 3 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.202A>G	p.Lys68Glu	missense	Exon 3 of 27	ENSP00000003084.6	P13569-1
	CFTR	ENST00000699605.1		c.-42A>G		5_prime_UTR_premature_start_codon_gain	Exon 4 of 27	ENSP00000514473.1	A0A8V8TPV6
	CFTR	ENST00000673785.1		c.-42A>G		5_prime_UTR_premature_start_codon_gain	Exon 6 of 13	ENSP00000501235.1	A0A669KBE8

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000159 AC: 40 AN: 251006 AF XY: 0.000251

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000917 AC: 134 AN: 1460654 Hom.: 2 Cov.: 29 AF XY: 0.000128 AC XY: 93 AN XY: 726724

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53134

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5758

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111228

Other (OTH) AF: 0.000249 AC: 15 AN: 60358

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74496

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.0000944 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.061	T
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.092
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.19	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.5
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.3	N
REVEL	Pathogenic	0.65
Sift	Uncertain	0.024	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.25	B
Vest4		0.90
MVP		0.98
MPC		0.0041
ClinPred		0.089	T
GERP RS		4.5
Varity_R		0.34
gMVP		0.88
Mutation Taster		=72/28	polymorphism

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: rs397508332; hg19: chr7-117149125;