chr6-52073547-TGAA-T
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2
The NM_138694.4(PKHD1):c.449-9_449-7delTTC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000525 in 1,555,584 control chromosomes in the GnomAD database, including 6 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_138694.4 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.449-9_449-7delTTC | splice_region_variant, intron_variant | Intron 6 of 66 | 1 | NM_138694.4 | ENSP00000360158.3 | |||
PKHD1 | ENST00000340994.4 | c.449-9_449-7delTTC | splice_region_variant, intron_variant | Intron 6 of 60 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes AF: 0.00284 AC: 432AN: 152196Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.000785 AC: 197AN: 250928Hom.: 2 AF XY: 0.000649 AC XY: 88AN XY: 135616
GnomAD4 exome AF: 0.000274 AC: 384AN: 1403270Hom.: 3 AF XY: 0.000231 AC XY: 162AN XY: 701954
GnomAD4 genome AF: 0.00284 AC: 433AN: 152314Hom.: 3 Cov.: 32 AF XY: 0.00275 AC XY: 205AN XY: 74482
ClinVar
Submissions by phenotype
not specified Benign:2
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Variant summary: PKHD1 c.449-9_449-7delTTC alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The variant allele was found at a frequency of 0.00096 in 121106 control chromosomes, predominantly at a frequency of 0.01 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease phenotype (0.0071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.449-9_449-7delTTC in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Autosomal recessive polycystic kidney disease Benign:2
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not provided Benign:1
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PKHD1-related disorder Benign:1
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Polycystic kidney disease 4 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at