2-85666719-C-T

Variant names:

• chr2-85666719-C-T
• rs34682912
• NM_000542.5:c.291G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000542.5(SFTPB):​c.291G>A​(p.Glu97Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00295 in 1,613,860 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (33 hom.)
• Consequence: SFTPB NM_000542.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.123

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-85666719-C-T is Benign according to our data. Variant chr2-85666719-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 165205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.123 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00274 (417/152180) while in subpopulation SAS AF= 0.00622 (30/4824). AF 95% confidence interval is 0.00448. There are 5 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SFTPB	NM_000542.5	c.291G>A	p.Glu97Glu	synonymous_variant	Exon 4 of 11	ENST00000519937.7	NP_000533.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPB	ENST00000519937.7	c.291G>A	p.Glu97Glu	synonymous_variant	Exon 4 of 11	1	NM_000542.5	ENSP00000428719.2

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 152062 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00303

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00384 AC: 965 AN: 251296 Hom.: 10 AF XY: 0.00431 AC XY: 585 AN XY: 135832

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00231

Gnomad ASJ exome AF: 0.0185

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00849

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00345

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00297 AC: 4345 AN: 1461680 Hom.: 33 Cov.: 35 AF XY: 0.00322 AC XY: 2344 AN XY: 727170

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.00257

Gnomad4 ASJ exome AF: 0.0177

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00777

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.00231

Gnomad4 OTH exome AF: 0.00513

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152180 Hom.: 5 Cov.: 32 AF XY: 0.00265 AC XY: 197 AN XY: 74394

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00622

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00303

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00333 Hom.: 2

Bravo AF: 0.00260

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.00453

EpiControl AF: 0.00468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Sep 21, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 21, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Glu109Glu in exon 5 of SFTPB: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.3% (26/8600) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs34682912). -

not provided Benign:2

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Surfactant metabolism dysfunction, pulmonary, 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary pulmonary alveolar proteinosis Benign:1

Sep 09, 2020

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
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.47

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

LitVar

Other links and lift over

dbSNP: rs34682912; hg19: chr2-85893842;