rs143832120
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_138694.4(PKHD1):c.6211A>C(p.Asn2071His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000697 in 1,613,216 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.6211A>C | p.Asn2071His | missense_variant | 38/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.6211A>C | p.Asn2071His | missense_variant | 38/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.6211A>C | p.Asn2071His | missense_variant | 38/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00256 AC: 390AN: 152062Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.00129 AC: 323AN: 251200Hom.: 2 AF XY: 0.00119 AC XY: 162AN XY: 135758
GnomAD4 exome AF: 0.000498 AC: 727AN: 1461036Hom.: 7 Cov.: 31 AF XY: 0.000509 AC XY: 370AN XY: 726856
GnomAD4 genome ? AF: 0.00261 AC: 397AN: 152180Hom.: 4 Cov.: 32 AF XY: 0.00227 AC XY: 169AN XY: 74404
ClinVar
Submissions by phenotype
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 26, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 02, 2020 | Variant summary: PKHD1 c.6211A>C (p.Asn2071His) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 282594 control chromosomes, predominantly at a frequency of 0.0093 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 1.32 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.6211A>C in individuals affected with Polycystic Kidney and Hepatic Disease and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Autosomal recessive polycystic kidney disease Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | May 11, 2017 | - - |
Polycystic kidney disease Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKHD1 p.Asn2071His variant was not identified in the literature nor was it identified in the LOVD 3.0, RWTH AAachen University ARPKD databases. The variant was identified in dbSNP (ID: rs143832120) as “With Likely benign allele”, ClinVar (as likely benign by Prevention Genetics), and Clinvitae (1x as likely benign). The variant was also identified in control databases in 380 of 276894 chromosomes at a frequency of 0.001372 in the following populations: African in 212 (2 homozygous) of 24024 chromosomes (freq. 0.0088), Ashkenazi Jewish in 46 of 10144 chromosomes (freq. 0.0045), South Asian in 78 (2 homozyogous) of 30782 chromsomes (freq. 0.0025), Other in 9 of 34354 chromosomes (freq. 0.0014), Latino in 20 of 34354 chromosomes (freq. 0.0006), and European (Non-Finnish) in 15 of 126500 chromosomes (freq. 0.0001), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Asn2071 residue is not conserved in mammals and the variant amino acid histidine (His) is present in many species including chimpanzees, macaques, dogs, and horses, increasing the likelihood that this variant does not have clinical significance. In addition, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory criteria to be classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at