rs1554392248

Variant names:

• chr7-117611722-CAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAGTATTATCC-TGTTAA
• rs1554392248
• NM_000492.4:c.3281_3367+268delCAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAGTATTATCCinsTGTTAA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PP2 PP5_Moderate

The NM_000492.4(CFTR):​c.3281_3367+268delCAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAGTATTATCCinsTGTTAA​(p.Ser1094_Gly1123delinsTer) variant causes a stop gained, splice donor, missense, disruptive inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S1094S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CFTR NM_000492.4 stop_gained, splice_donor, missense, disruptive_inframe_deletion, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.89
• Publications: 0 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• 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)

ENSG00000083622 (HGNC:40145):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• 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.
• PP5: Variant 7-117611722-CAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAGTATTATCC-TGTTAA is Pathogenic according to our data. Variant chr7-117611722-CAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAGTATTATCC-TGTTAA is described in ClinVar as Pathogenic. ClinVar VariationId is 53703.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3281_3367+268delCAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAGTATTATCCinsTGTTAA	p.Ser1094_Gly1123delinsTer	stop_gained, splice_donor_variant, missense_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant		ENST00000003084.11	NP_000483.3
CFTR-AS2	NR_199597.1	n.177+4153_177+4507delGGATAATACTATATATATATATGTATATATATATATATATATATATATATATACATATATATATATATATCCGATTTCAAGGAAATTATTTGTTTAACAATAAAACAATGGAAATTCAAAGAAATCACTTGTTCAATAATAAACCAACAAATTTGTTAATTACTAAACTCTAAAGATATCAAAAATTGATAACCTATAGAATGCAGCATTTTATTCATTGAAAATTTTTTACTTAAATGCTTAGCTAAAGTTAATGAGTTCATAGTACCTGTTGTTAAAATGGAAATGAAGGTAACAGCAATGAAGAAGATGACAAAAATCATTTCTATTCTCATTTGGAACCAGCGCAGTGTTGinsTTAACA		intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3281_3367+268delCAACACTGCGCTGGTTCCAAATGAGAATAGAAATGATTTTTGTCATCTTCTTCATTGCTGTTACCTTCATTTCCATTTTAACAACAGGTACTATGAACTCATTAACTTTAGCTAAGCATTTAAGTAAAAAATTTTCAATGAATAAAATGCTGCATTCTATAGGTTATCAATTTTTGATATCTTTAGAGTTTAGTAATTAACAAATTTGTTGGTTTATTATTGAACAAGTGATTTCTTTGAATTTCCATTGTTTTATTGTTAAACAAATAATTTCCTTGAAATCGGATATATATATATATATGTATATATATATATATATATATATATATATACATATATATATATAGTATTATCCinsTGTTAA	p.Ser1094_Gly1123delinsTer	stop_gained, splice_donor_variant, missense_variant, disruptive_inframe_deletion, splice_region_variant, intron_variant		1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cystic fibrosis Pathogenic:1 Other:1

Dec 23, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: This CFTR c.3281_3367+268delinsTGTTAA variant leads to a partial deletion of exon 20 as well as the overlapping the splice-donor site. This would either lead to a deletion of 28 amino acids from exon 20 and subsequently would be predicted to impact protein function or disrupt normal splicing. The frequency of this variant in the general population could not be determined as the technology used for large population databases (ExAC, gnomAD, ESP, 1000G) cannot detect variants of this type. c.3281_3367+268delinsTGTTAA has been reported in the literature in individuals affected with Cystic Fibrosis (Niel_2004; Ferec_2006) as we reputed databases (sick kids) that cited this variant as having been identified on the maternal chromosome of a 10 year old boy who was diagnosed with CF at 1 year because of failure to thrive. He was reported as pancreatically insufficient, lung colonization with Pseudomonas aeruginosa. His sweat test was reportedly clearly positive. He carried p.F508del on the other chromosome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Furthermore, another deletion variant which involves complete deletion of exon 20 has also been reported in a CF patient (PMID: 8682493). No other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as pathogenic. -

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ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9

Splicing

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

Other links and lift over

dbSNP: rs1554392248; hg19: chr7-117251776;