chr12-12138704-C-T

Variant names:

• chr12-12138704-C-T
• rs7980903
• NM_002336.3:c.3398-170G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002336.3(LRP6):​c.3398-170G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.825 in 1,354,246 control chromosomes in the GnomAD database, including 461,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.84 (54170 hom., cov: 32)
  • Exomes 𝑓: 0.82 (407527 hom.)
• Consequence: LRP6 NM_002336.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0220

Genes affected

LRP6 (HGNC:6698): (LDL receptor related protein 6) This gene encodes a member of the low density lipoprotein (LDL) receptor gene family. LDL receptors are transmembrane cell surface proteins involved in receptor-mediated endocytosis of lipoprotein and protein ligands. The protein encoded by this gene functions as a receptor or, with Frizzled, a co-receptor for Wnt and thereby transmits the canonical Wnt/beta-catenin signaling cascade. Through its interaction with the Wnt/beta-catenin signaling cascade this gene plays a role in the regulation of cell differentiation, proliferation, and migration and the development of many cancer types. This protein undergoes gamma-secretase dependent RIP- (regulated intramembrane proteolysis) processing but the precise locations of the cleavage sites have not been determined.[provided by RefSeq, Dec 2009]

BCL2L14 (HGNC:16657): (BCL2 like 14) The protein encoded by this gene belongs to the BCL2 protein family. BCL2 family members form hetero- or homodimers and act as anti- or pro-apoptotic regulators that are involved in a wide variety of cellular activities. Overexpression of this gene has been shown to induce apoptosis in cells. Three alternatively spliced transcript variants encoding two distinct isoforms have been reported for this gene. [provided by RefSeq, May 2009]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 12-12138704-C-T is Benign according to our data. Variant chr12-12138704-C-T is described in ClinVar as [Benign]. Clinvar id is 1239183.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRP6	NM_002336.3	c.3398-170G>A		intron_variant	Intron 15 of 22	ENST00000261349.9	NP_002327.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRP6	ENST00000261349.9	c.3398-170G>A		intron_variant	Intron 15 of 22	1	NM_002336.3	ENSP00000261349.4
LRP6	ENST00000543091.1	c.3398-170G>A		intron_variant	Intron 15 of 22	1		ENSP00000442472.1
LRP6	ENST00000538239.5	n.2990-170G>A		intron_variant	Intron 14 of 23	1		ENSP00000445083.1
BCL2L14	ENST00000298566.2	n.712-132C>T		intron_variant	Intron 4 of 6	2		ENSP00000298566.1

Frequencies

GnomAD3 genomes AF: 0.843 AC: 128108 AN: 152050 Hom.: 54128 Cov.: 32

Gnomad AFR AF: 0.871

Gnomad AMI AF: 0.734

Gnomad AMR AF: 0.889

Gnomad ASJ AF: 0.864

Gnomad EAS AF: 0.931

Gnomad SAS AF: 0.892

Gnomad FIN AF: 0.811

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.810

Gnomad OTH AF: 0.853

GnomAD4 exome AF: 0.823 AC: 988792 AN: 1202078 Hom.: 407527 Cov.: 16 AF XY: 0.825 AC XY: 494366 AN XY: 599572

African (AFR) AF: 0.870 AC: 22834 AN: 26256

American (AMR) AF: 0.910 AC: 23595 AN: 25916

Ashkenazi Jewish (ASJ) AF: 0.866 AC: 18364 AN: 21214

East Asian (EAS) AF: 0.941 AC: 32909 AN: 34986

South Asian (SAS) AF: 0.887 AC: 59850 AN: 67500

European-Finnish (FIN) AF: 0.817 AC: 38721 AN: 47396

Middle Eastern (MID) AF: 0.836 AC: 2935 AN: 3510

European-Non Finnish (NFE) AF: 0.808 AC: 747295 AN: 924738

Other (OTH) AF: 0.836 AC: 42289 AN: 50562

GnomAD4 genome AF: 0.843 AC: 128209 AN: 152168 Hom.: 54170 Cov.: 32 AF XY: 0.846 AC XY: 62934 AN XY: 74382

African (AFR) AF: 0.871 AC: 36138 AN: 41502

American (AMR) AF: 0.889 AC: 13589 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 3000 AN: 3472

East Asian (EAS) AF: 0.931 AC: 4831 AN: 5190

South Asian (SAS) AF: 0.891 AC: 4296 AN: 4820

European-Finnish (FIN) AF: 0.811 AC: 8570 AN: 10564

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.810 AC: 55069 AN: 68010

Other (OTH) AF: 0.854 AC: 1806 AN: 2114

Alfa AF: 0.824 Hom.: 25051

Bravo AF: 0.849

Asia WGS AF: 0.906 AC: 3151 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.1
DANN	Benign	0.18
PhyloP100		0.022
Mutation Taster		=100/0	polymorphism (auto)

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

Publications

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Other links and lift over

dbSNP: rs7980903; hg19: chr12-12291638;