NM_001270987.2:c.39+1896T>C

Variant names:

• chr12-6377490-T-C
• rs879605
• NM_001270987.2:c.39+1896T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 publications found

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]

SCNN1A Gene-Disease associations (from GenCC):

• pseudohypoaldosteronism, type IB1, autosomal recessive

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Laboratory for Molecular Medicine, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• bronchiectasis with or without elevated sweat chloride 2

  Inheritance: Unknown, AD Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• Brugada syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Liddle syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Liddle syndrome 3

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
LTBR	NM_001270987.2	c.39+1896T>C		intron_variant	Intron 1 of 9		NP_001257916.1
LTBR	NM_001414309.1	c.39+1896T>C		intron_variant	Intron 1 of 9		NP_001401238.1
SCNN1A	NM_001159575.2	c.-224A>G		upstream_gene_variant			NP_001153047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTBR	ENST00000539925.5	c.39+1896T>C		intron_variant	Intron 1 of 9	2		ENSP00000440875.1
SCNN1A	ENST00000536788.1	c.9+177A>G		intron_variant	Intron 1 of 1	4		ENSP00000443434.1
SCNN1A	ENST00000538957.1	n.23-139A>G		intron_variant	Intron 1 of 2	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

African (AFR) AF: 0.0951 AC: 1308 AN: 13750

American (AMR) AF: 0.151 AC: 3449 AN: 22896

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 1800 AN: 14622

East Asian (EAS) AF: 0.0649 AC: 1937 AN: 29852

South Asian (SAS) AF: 0.224 AC: 11280 AN: 50354

European-Finnish (FIN) AF: 0.261 AC: 7277 AN: 27878

Middle Eastern (MID) AF: 0.0998 AC: 210 AN: 2104

European-Non Finnish (NFE) AF: 0.223 AC: 71240 AN: 320178

Other (OTH) AF: 0.177 AC: 4864 AN: 27438

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

African (AFR) AF: 0.0966 AC: 4011 AN: 41522

American (AMR) AF: 0.148 AC: 2262 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 468 AN: 3464

East Asian (EAS) AF: 0.0736 AC: 382 AN: 5192

South Asian (SAS) AF: 0.227 AC: 1095 AN: 4816

European-Finnish (FIN) AF: 0.264 AC: 2797 AN: 10588

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14987 AN: 67994

Other (OTH) AF: 0.142 AC: 300 AN: 2110

Alfa AF: 0.200 Hom.: 5507

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

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.16
PhyloP100		-0.22
PromoterAI		0.47	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs879605; hg19: chr12-6486656;