chr15-96332202-CCGCCCGG-C

Variant names:

• chr15-96332202-CCGCCCGG-C
• rs1899167400
• NM_021005.4:c.103_109delGGCGCCC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_021005.4(NR2F2):​c.103_109delGGCGCCC​(p.Gly35ArgfsTer75) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NR2F2 NM_021005.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.90

Genes affected

NR2F2 (HGNC:7976): (nuclear receptor subfamily 2 group F member 2) This gene encodes a member of the steroid thyroid hormone superfamily of nuclear receptors. The encoded protein is a ligand inducible transcription factor that is involved in the regulation of many different genes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-96332202-CCGCCCGG-C is Pathogenic according to our data. Variant chr15-96332202-CCGCCCGG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 916038.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr15-96332202-CCGCCCGG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR2F2	NM_021005.4	c.103_109delGGCGCCC	p.Gly35ArgfsTer75	frameshift_variant	Exon 1 of 3	ENST00000394166.8	NP_066285.1
NR2F2	NM_001145155.2	c.44-1868_44-1862delGGCGCCC		intron_variant	Intron 1 of 2		NP_001138627.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR2F2	ENST00000394166.8	c.103_109delGGCGCCC	p.Gly35ArgfsTer75	frameshift_variant	Exon 1 of 3	1	NM_021005.4	ENSP00000377721.3
NR2F2	ENST00000421109.6	c.44-1868_44-1862delGGCGCCC		intron_variant	Intron 1 of 2	1		ENSP00000401674.2

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

46,xx sex reversal 5 Pathogenic:2

Jun 02, 2020

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Aug 18, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been previously reported as de novo in a similarly affected individual (PMID: 29478779). The variant has been reported to be associated with NR2F2 related disorder (ClinVar ID: VCV000916038 /PMID: 29478779). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided Pathogenic:1

Dec 05, 2019

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1899167400; hg19: chr15-96875431;