2-85668215-T-G

Variant names:

• chr2-85668215-T-G
• rs2077079
• ENST00000393822.7:c.-32A>C

Variant summary

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

The ENST00000393822.7(SFTPB):​c.-32A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.391 in 1,548,004 control chromosomes in the GnomAD database, including 119,398 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12030 hom., cov: 33)
  • Exomes 𝑓: 0.39 (107368 hom.)
• Consequence: SFTPB ENST00000393822.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.28
• Publications: 43 publications found

Genes affected

SFTPB (HGNC:10801): (surfactant protein B) This gene encodes the pulmonary-associated surfactant protein B (SPB), an amphipathic surfactant protein essential for lung function and homeostasis after birth. Pulmonary surfactant is a surface-active lipoprotein complex composed of 90% lipids and 10% proteins which include plasma proteins and apolipoproteins SPA, SPB, SPC and SPD. The surfactant is secreted by the alveolar cells of the lung and maintains the stability of pulmonary tissue by reducing the surface tension of fluids that coat the lung. The SPB enhances the rate of spreading and increases the stability of surfactant monolayers in vitro. Multiple mutations in this gene have been identified, which cause pulmonary surfactant metabolism dysfunction type 1, also called pulmonary alveolar proteinosis due to surfactant protein B deficiency, and are associated with fatal respiratory distress in the neonatal period. Alternatively spliced transcript variants encoding the same protein have been identified.[provided by RefSeq, Feb 2010]

SFTPB Gene-Disease associations (from GenCC):

• surfactant metabolism dysfunction, pulmonary, 1

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.3776293E-4).
• BP6: Variant 2-85668215-T-G is Benign according to our data. Variant chr2-85668215-T-G is described in ClinVar as Benign. ClinVar VariationId is 165208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPB	NM_000542.5	c.-32A>C		upstream_gene_variant		ENST00000519937.7	NP_000533.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPB	ENST00000519937.7	c.-32A>C		upstream_gene_variant		1	NM_000542.5	ENSP00000428719.2

Frequencies

GnomAD3 genomes AF: 0.395 AC: 59945 AN: 151856 Hom.: 12028 Cov.: 33

Gnomad AFR AF: 0.386

Gnomad AMI AF: 0.469

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.495

Gnomad EAS AF: 0.508

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.500

Gnomad NFE AF: 0.388

Gnomad OTH AF: 0.401

GnomAD2 exomes AF: 0.411 AC: 63998 AN: 155794 AF XY: 0.413

Gnomad AFR exome AF: 0.370

Gnomad AMR exome AF: 0.439

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.503

Gnomad FIN exome AF: 0.318

Gnomad NFE exome AF: 0.387

Gnomad OTH exome AF: 0.410

GnomAD4 exome AF: 0.390 AC: 544541 AN: 1396030 Hom.: 107368 Cov.: 33 AF XY: 0.393 AC XY: 270236 AN XY: 688432

African (AFR) AF: 0.375 AC: 11823 AN: 31530

American (AMR) AF: 0.444 AC: 15849 AN: 35682

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 12457 AN: 25168

East Asian (EAS) AF: 0.507 AC: 18095 AN: 35694

South Asian (SAS) AF: 0.444 AC: 35136 AN: 79132

European-Finnish (FIN) AF: 0.312 AC: 15364 AN: 49202

Middle Eastern (MID) AF: 0.435 AC: 2281 AN: 5248

European-Non Finnish (NFE) AF: 0.381 AC: 410612 AN: 1076550

Other (OTH) AF: 0.396 AC: 22924 AN: 57824

GnomAD4 genome AF: 0.395 AC: 59972 AN: 151974 Hom.: 12030 Cov.: 33 AF XY: 0.393 AC XY: 29193 AN XY: 74296

African (AFR) AF: 0.385 AC: 15957 AN: 41438

American (AMR) AF: 0.411 AC: 6281 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.495 AC: 1717 AN: 3470

East Asian (EAS) AF: 0.510 AC: 2620 AN: 5142

South Asian (SAS) AF: 0.454 AC: 2186 AN: 4810

European-Finnish (FIN) AF: 0.323 AC: 3416 AN: 10578

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.388 AC: 26371 AN: 67936

Other (OTH) AF: 0.402 AC: 849 AN: 2112

Alfa AF: 0.401 Hom.: 16176

Bravo AF: 0.403

TwinsUK AF: 0.369 AC: 1368

ALSPAC AF: 0.362 AC: 1396

ESP6500AA AF: 0.345 AC: 1343

ESP6500EA AF: 0.354 AC: 2642

ExAC AF: 0.309 AC: 11819

Asia WGS AF: 0.457 AC: 1588 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

-

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

This variant is associated with the following publications: (PMID: 26202972, 17071721) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Jun 13, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Surfactant metabolism dysfunction, pulmonary, 1 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary pulmonary alveolar proteinosis Benign:1

Oct 26, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	13
DANN	Benign	0.20
DEOGEN2	Benign	0.0052	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.00081	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.00024	T
MetaSVM	Benign	-0.92	T
PhyloP100		1.3
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.030
Sift	Benign	0.66	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.24
ClinPred		0.00099	T
GERP RS		2.5
PromoterAI		0.032	Neutral
gMVP		0.51
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs2077079; hg19: chr2-85895338; COSMIC: COSV60893938; COSMIC: COSV60893938;