chr12-6377490-T-C

Position:

• chr12-6377490-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001270987.2(LTBR):​c.39+1896T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 661,246 control chromosomes in the GnomAD database, including 14,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2680 hom., cov: 32)
  • Exomes 𝑓: 0.20 (11532 hom.)
• Consequence: LTBR NM_001270987.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.223

Genes affected

LTBR (HGNC:6718): (lymphotoxin beta receptor) This gene encodes a member of the tumor necrosis factor receptor superfamily. The major ligands of this receptor include lymphotoxin alpha/beta and tumor necrosis factor ligand superfamily member 14. The encoded protein plays a role in signalling during the development of lymphoid and other organs, lipid metabolism, immune response, and programmed cell death. Activity of this receptor has also been linked to carcinogenesis. Alternatively spliced transcript variants encoding multiple isoforms have been observed. [provided by RefSeq, Aug 2012]

SCNN1A (HGNC:10599): (sodium channel epithelial 1 subunit alpha) Nonvoltage-gated, amiloride-sensitive, sodium channels control fluid and electrolyte transport across epithelia in many organs. These channels are heteromeric complexes consisting of 3 subunits: alpha, beta, and gamma. This gene encodes the alpha subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), a rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-6377490-T-C is Benign according to our data. Variant chr12-6377490-T-C is described in ClinVar as [Benign]. Clinvar id is 1242331.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.217 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LTBR	NM_001270987.2	c.39+1896T>C		intron_variant			NP_001257916.1
LTBR	NM_001414309.1	c.39+1896T>C		intron_variant			NP_001401238.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SCNN1A	ENST00000536788.1	c.9+177A>G		intron_variant		4		ENSP00000443434
LTBR	ENST00000539925.5	c.39+1896T>C		intron_variant		2		ENSP00000440875	A2
SCNN1A	ENST00000538957.1	n.23-139A>G		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26592 AN: 152056 Hom.: 2681 Cov.: 32

Gnomad AFR AF: 0.0965

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.0736

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.264

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.220

Gnomad OTH AF: 0.143

GnomAD4 exome AF: 0.203 AC: 103365 AN: 509072 Hom.: 11532 AF XY: 0.204 AC XY: 54478 AN XY: 267230

Gnomad4 AFR exome AF: 0.0951

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.123

Gnomad4 EAS exome AF: 0.0649

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.261

Gnomad4 NFE exome AF: 0.223

Gnomad4 OTH exome AF: 0.177

GnomAD4 genome AF: 0.175 AC: 26605 AN: 152174 Hom.: 2680 Cov.: 32 AF XY: 0.176 AC XY: 13105 AN XY: 74412

Gnomad4 AFR AF: 0.0966

Gnomad4 AMR AF: 0.148

Gnomad4 ASJ AF: 0.135

Gnomad4 EAS AF: 0.0736

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.264

Gnomad4 NFE AF: 0.220

Gnomad4 OTH AF: 0.142

Alfa AF: 0.200 Hom.: 865

Bravo AF: 0.161

Asia WGS AF: 0.136 AC: 474 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.16

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs879605; hg19: chr12-6486656;