NM_138694.4:c.8643-24A>G

Variant names:

• chr6-51754962-T-C
• rs2766125
• NM_138694.4:c.8643-24A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_138694.4(PKHD1):​c.8643-24A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0159 in 1,600,350 control chromosomes in the GnomAD database, including 1,565 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.054 (654 hom., cov: 32)
  • Exomes 𝑓: 0.012 (911 hom.)
• Consequence: PKHD1 NM_138694.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.401
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Genomics England PanelApp
• Caroli disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-51754962-T-C is Benign according to our data. Variant chr6-51754962-T-C is described in ClinVar as Benign. ClinVar VariationId is 262422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	NM_138694.4	MANE Select	c.8643-24A>G		intron	N/A	NP_619639.3
	PKHD1	NM_170724.3		c.8643-24A>G		intron	N/A	NP_733842.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKHD1	ENST00000371117.8	TSL:1 MANE Select	c.8643-24A>G		intron	N/A	ENSP00000360158.3
	PKHD1	ENST00000340994.4	TSL:5	c.8643-24A>G		intron	N/A	ENSP00000341097.4

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 8208 AN: 152074 Hom.: 651 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0198

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0602

Gnomad SAS AF: 0.0745

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0449

GnomAD2 exomes AF: 0.0267 AC: 6679 AN: 250032 AF XY: 0.0254

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.0596

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.0162

GnomAD4 exome AF: 0.0119 AC: 17206 AN: 1448158 Hom.: 911 Cov.: 29 AF XY: 0.0130 AC XY: 9350 AN XY: 721504

African (AFR) AF: 0.175 AC: 5800 AN: 33064

American (AMR) AF: 0.0127 AC: 568 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00161 AC: 42 AN: 26018

East Asian (EAS) AF: 0.0599 AC: 2371 AN: 39606

South Asian (SAS) AF: 0.0669 AC: 5754 AN: 85968

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53384

Middle Eastern (MID) AF: 0.0243 AC: 139 AN: 5730

European-Non Finnish (NFE) AF: 0.00105 AC: 1158 AN: 1099834

Other (OTH) AF: 0.0227 AC: 1358 AN: 59888

GnomAD4 genome AF: 0.0541 AC: 8232 AN: 152192 Hom.: 654 Cov.: 32 AF XY: 0.0536 AC XY: 3989 AN XY: 74380

African (AFR) AF: 0.170 AC: 7065 AN: 41510

American (AMR) AF: 0.0197 AC: 301 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.0603 AC: 312 AN: 5172

South Asian (SAS) AF: 0.0746 AC: 359 AN: 4814

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00126 AC: 86 AN: 68016

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0281 Hom.: 136

Bravo AF: 0.0603

Asia WGS AF: 0.0980 AC: 341 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive polycystic kidney disease (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.0
DANN	Benign	0.60
PhyloP100		-0.40
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2766125; hg19: chr6-51619760; COSMIC: COSV61885922;