rs41274951

Variant names:

• chr9-100296894-C-G
• rs41274951
• NM_014425.5:c.2787-23C>G

Your query was ambiguous. Multiple possible variants found:

• chr9-100296894-C-G
• chr9-100296894-C-T

Variant summary

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

The NM_014425.5(INVS):​c.2787-23C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,589,220 control chromosomes in the GnomAD database, including 16,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1400 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15485 hom.)
• Consequence: INVS NM_014425.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0350
• Publications: 3 publications found

Genes affected

INVS (HGNC:17870): (inversin) This gene encodes a protein containing multiple ankyrin domains and two IQ calmodulin-binding domains. The encoded protein may function in renal tubular development and function, and in left-right axis determination. This protein interacts with nephrocystin and infers a connection between primary cilia function and left-right axis determination. A similar protein in mice interacts with calmodulin. Mutations in this gene have been associated with nephronophthisis type 2. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, May 2012]

INVS Gene-Disease associations (from GenCC):

• nephronophthisis 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, 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=-0.72).
• BP6: Variant 9-100296894-C-G is Benign according to our data. Variant chr9-100296894-C-G is described in ClinVar as Benign. ClinVar VariationId is 260413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INVS	NM_014425.5	c.2787-23C>G		intron_variant	Intron 14 of 16	ENST00000262457.7	NP_055240.2
INVS	NM_001318381.2	c.2499-23C>G		intron_variant	Intron 15 of 17		NP_001305310.1
INVS	NM_001318382.2	c.1809-23C>G		intron_variant	Intron 14 of 16		NP_001305311.1
INVS	NR_134606.2	n.2936-23C>G		intron_variant	Intron 14 of 16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INVS	ENST00000262457.7	c.2787-23C>G		intron_variant	Intron 14 of 16	1	NM_014425.5	ENSP00000262457.2
INVS	ENST00000262456.6	c.2277-23C>G		intron_variant	Intron 15 of 17	5		ENSP00000262456.2

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20177 AN: 152050 Hom.: 1402 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.0678

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0616

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.121

GnomAD2 exomes AF: 0.113 AC: 28143 AN: 249686 AF XY: 0.113

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.0678

Gnomad ASJ exome AF: 0.0698

Gnomad EAS exome AF: 0.000491

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.151

Gnomad OTH exome AF: 0.120

GnomAD4 exome AF: 0.141 AC: 202549 AN: 1437052 Hom.: 15485 Cov.: 28 AF XY: 0.139 AC XY: 99303 AN XY: 716346

African (AFR) AF: 0.134 AC: 4407 AN: 32942

American (AMR) AF: 0.0732 AC: 3261 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.0704 AC: 1830 AN: 25988

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39558

South Asian (SAS) AF: 0.0683 AC: 5843 AN: 85514

European-Finnish (FIN) AF: 0.141 AC: 7550 AN: 53366

Middle Eastern (MID) AF: 0.108 AC: 618 AN: 5730

European-Non Finnish (NFE) AF: 0.157 AC: 171012 AN: 1089870

Other (OTH) AF: 0.135 AC: 8016 AN: 59530

GnomAD4 genome AF: 0.133 AC: 20191 AN: 152168 Hom.: 1400 Cov.: 32 AF XY: 0.129 AC XY: 9590 AN XY: 74384

African (AFR) AF: 0.136 AC: 5647 AN: 41516

American (AMR) AF: 0.115 AC: 1761 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0678 AC: 235 AN: 3468

East Asian (EAS) AF: 0.000969 AC: 5 AN: 5162

South Asian (SAS) AF: 0.0614 AC: 296 AN: 4820

European-Finnish (FIN) AF: 0.151 AC: 1601 AN: 10608

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10258 AN: 67998

Other (OTH) AF: 0.119 AC: 252 AN: 2112

Alfa AF: 0.133 Hom.: 247

Bravo AF: 0.130

Asia WGS AF: 0.0360 AC: 128 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	2.9
DANN	Benign	0.74
PhyloP100		0.035
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs41274951; hg19: chr9-103059176;