rs2271244

Variant names:

• chr2-110161744-C-T
• rs2271244
• NM_001128178.3:c.860-47G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-110161744-C-T
• chr2-110161744-C-A

Variant summary

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

The NM_001128178.3(NPHP1):​c.860-47G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,368,978 control chromosomes in the GnomAD database, including 80,554 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7601 hom., cov: 32)
  • Exomes 𝑓: 0.34 (72953 hom.)
• Consequence: NPHP1 NM_001128178.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.185
• Publications: 9 publications found

Genes affected

NPHP1 (HGNC:7905): (nephrocystin 1) This gene encodes a protein with src homology domain 3 (SH3) patterns. This protein interacts with Crk-associated substrate, and it appears to function in the control of cell division, as well as in cell-cell and cell-matrix adhesion signaling, likely as part of a multifunctional complex localized in actin- and microtubule-based structures. Mutations in this gene cause familial juvenile nephronophthisis type 1, a kidney disorder involving both tubules and glomeruli. Defects in this gene are also associated with Senior-Loken syndrome type 1, also referred to as juvenile nephronophthisis with Leber amaurosis, which is characterized by kidney and eye disease, and with Joubert syndrome type 4, which is characterized by cerebellar ataxia, oculomotor apraxia, psychomotor delay and neonatal breathing abnormalities, sometimes including retinal dystrophy and renal disease. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

NPHP1 Gene-Disease associations (from GenCC):

• Joubert syndrome with renal defect

  Inheritance: AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, G2P
• nephronophthisis 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Senior-Loken syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 2-110161744-C-T is Benign according to our data. Variant chr2-110161744-C-T is described in ClinVar as Benign. ClinVar VariationId is 255705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.544 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001128178.3. 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
	NPHP1	NM_001128178.3	MANE Select	c.860-47G>A		intron	N/A	NP_001121650.1	O15259-2
	NPHP1	NM_000272.5		c.1028-47G>A		intron	N/A	NP_000263.2
	NPHP1	NM_207181.4		c.1025-47G>A		intron	N/A	NP_997064.2	O15259-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPHP1	ENST00000445609.7	TSL:1 MANE Select	c.860-47G>A		intron	N/A	ENSP00000389879.3	O15259-2
	NPHP1	ENST00000316534.8	TSL:1	c.1028-47G>A		intron	N/A	ENSP00000313169.4	O15259-4
	NPHP1	ENST00000393272.7	TSL:1	c.1025-47G>A		intron	N/A	ENSP00000376953.3	O15259-1

Frequencies

GnomAD3 genomes AF: 0.301 AC: 45716 AN: 151782 Hom.: 7583 Cov.: 32

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.348

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.389

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.309

GnomAD2 exomes AF: 0.354 AC: 77416 AN: 218922 AF XY: 0.363

Gnomad AFR exome AF: 0.203

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.576

Gnomad FIN exome AF: 0.229

Gnomad NFE exome AF: 0.329

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.337 AC: 409664 AN: 1217078 Hom.: 72953 Cov.: 16 AF XY: 0.342 AC XY: 210951 AN XY: 616158

African (AFR) AF: 0.201 AC: 5686 AN: 28298

American (AMR) AF: 0.349 AC: 14748 AN: 42266

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 7681 AN: 24492

East Asian (EAS) AF: 0.579 AC: 21670 AN: 37458

South Asian (SAS) AF: 0.490 AC: 38716 AN: 79014

European-Finnish (FIN) AF: 0.230 AC: 11754 AN: 51206

Middle Eastern (MID) AF: 0.372 AC: 1959 AN: 5264

European-Non Finnish (NFE) AF: 0.323 AC: 289976 AN: 896990

Other (OTH) AF: 0.335 AC: 17474 AN: 52090

GnomAD4 genome AF: 0.301 AC: 45783 AN: 151900 Hom.: 7601 Cov.: 32 AF XY: 0.306 AC XY: 22688 AN XY: 74250

African (AFR) AF: 0.203 AC: 8433 AN: 41442

American (AMR) AF: 0.372 AC: 5686 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1091 AN: 3470

East Asian (EAS) AF: 0.561 AC: 2886 AN: 5140

South Asian (SAS) AF: 0.493 AC: 2373 AN: 4812

European-Finnish (FIN) AF: 0.224 AC: 2356 AN: 10520

Middle Eastern (MID) AF: 0.394 AC: 115 AN: 292

European-Non Finnish (NFE) AF: 0.322 AC: 21874 AN: 67936

Other (OTH) AF: 0.309 AC: 654 AN: 2114

Alfa AF: 0.318 Hom.: 6034

Bravo AF: 0.303

Asia WGS AF: 0.479 AC: 1665 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.2
DANN	Benign	0.69
PhyloP100		0.18
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: rs2271244; hg19: chr2-110919321;