rs143832120

chr6-51912487-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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:
  • Genomes: 𝑓 0.0026 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (7 hom.)
• Consequence: PKHD1 NM_138694.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.41

Genes affected

PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008208722).
• BP6: Variant 6-51912487-T-G is Benign according to our data. Variant chr6-51912487-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 262408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51912487-T-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 4 AR gene

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: 390 AN: 152062 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000721

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00129 AC: 323 AN: 251200 Hom.: 2 AF XY: 0.00119 AC XY: 162 AN XY: 135758

Gnomad AFR exome AF: 0.00979

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000498 AC: 727 AN: 1461036 Hom.: 7 Cov.: 31 AF XY: 0.000509 AC XY: 370 AN XY: 726856

Gnomad4 AFR exome AF: 0.00819

Gnomad4 AMR exome AF: 0.000627

Gnomad4 ASJ exome AF: 0.00502

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00183

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000720

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152180 Hom.: 4 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74404

Gnomad4 AFR AF: 0.00860

Gnomad4 AMR AF: 0.000720

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000695 Hom.: 0

Bravo AF: 0.00303

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00146 AC: 177

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

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	PreventionGenetics, part of Exact Sciences	-	- -
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. -

Autosomal recessive polycystic kidney disease Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 11, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	11
Dann	Benign	0.92
DEOGEN2	Benign	0.088	T;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.080	T;T
MetaRNN	Benign	0.0082	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-1.8	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.81	N;N
REVEL	Benign	0.18
Sift	Benign	0.55	T;T
Sift4G	Benign	0.77	T;T
Polyphen		0.0	B;B
Vest4		0.19
MVP		0.63
MPC		0.061
ClinPred		0.0028	T
GERP RS		4.2
Varity_R		0.043
gMVP		0.28

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

Publications

LitVar

Other links and lift over

dbSNP: rs143832120; hg19: chr6-51777285;