NM_138694.4:c.*2553delA

Variant names:

• chr6-51616527-AT-A
• rs113144792
• NM_138694.4:c.*2553delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_138694.4(PKHD1):​c.*2553delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.189 in 348,952 control chromosomes in the GnomAD database, including 44 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.020 (42 hom., cov: 28)
  • Exomes 𝑓: 0.30 (2 hom.)
• Consequence: PKHD1 NM_138694.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0790
• Publications: 1 publications found

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]

PKHD1 Gene-Disease associations (from GenCC):

• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Myriad Women’s Health, Orphanet
• polycystic kidney disease 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000228689 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.05 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138694.4. 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
	PKHD1	NM_138694.4	MANE Select	c.*2553delA		3_prime_UTR	Exon 67 of 67	NP_619639.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.*2553delA		3_prime_UTR	Exon 67 of 67	ENSP00000360158.3	P08F94-1
	ENSG00000228689	ENST00000454361.1	TSL:3	n.81-5813delT		intron	N/A
	ENSG00000228689	ENST00000589278.6	TSL:5	n.811-5818delT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 2807 AN: 140834 Hom.: 41 Cov.: 28

Gnomad AFR AF: 0.0518

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00455

Gnomad EAS AF: 0.00841

Gnomad SAS AF: 0.00554

Gnomad FIN AF: 0.0190

Gnomad MID AF: 0.0233

Gnomad NFE AF: 0.00591

Gnomad OTH AF: 0.0142

GnomAD4 exome AF: 0.304 AC: 63257 AN: 208072 Hom.: 2 Cov.: 0 AF XY: 0.305 AC XY: 32212 AN XY: 105526

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.316 AC: 1946 AN: 6152

American (AMR) AF: 0.319 AC: 2025 AN: 6354

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 2352 AN: 7756

East Asian (EAS) AF: 0.272 AC: 5399 AN: 19834

South Asian (SAS) AF: 0.312 AC: 609 AN: 1952

European-Finnish (FIN) AF: 0.298 AC: 5141 AN: 17236

Middle Eastern (MID) AF: 0.336 AC: 358 AN: 1066

European-Non Finnish (NFE) AF: 0.307 AC: 41179 AN: 133950

Other (OTH) AF: 0.308 AC: 4248 AN: 13772

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0200 AC: 2818 AN: 140880 Hom.: 42 Cov.: 28 AF XY: 0.0209 AC XY: 1425 AN XY: 68210

African (AFR) AF: 0.0519 AC: 1996 AN: 38454

American (AMR) AF: 0.0117 AC: 163 AN: 13984

Ashkenazi Jewish (ASJ) AF: 0.00455 AC: 15 AN: 3296

East Asian (EAS) AF: 0.00843 AC: 41 AN: 4864

South Asian (SAS) AF: 0.00533 AC: 23 AN: 4312

European-Finnish (FIN) AF: 0.0190 AC: 164 AN: 8618

Middle Eastern (MID) AF: 0.0288 AC: 8 AN: 278

European-Non Finnish (NFE) AF: 0.00591 AC: 380 AN: 64276

Other (OTH) AF: 0.0146 AC: 28 AN: 1918

Alfa AF: 0.000889 Hom.: 17

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.079
Mutation Taster		=100/0	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: rs113144792; hg19: chr6-51481325; COSMIC: COSV64380809;