2-85665659-C-T

Variant names:

• chr2-85665659-C-T
• rs34550459
• NM_000542.5:c.529G>A

Variant summary

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

The NM_000542.5(SFTPB):​c.529G>A​(p.Val177Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,614,108 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0063 (45 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (292 hom.)
• Consequence: SFTPB NM_000542.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.0820
• Publications: 5 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=0.002817452).
• BP6: Variant 2-85665659-C-T is Benign according to our data. Variant chr2-85665659-C-T is described in ClinVar as Benign. ClinVar VariationId is 227072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0525 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000542.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPB	NM_000542.5	MANE Select	c.529G>A	p.Val177Ile	missense	Exon 5 of 11	NP_000533.4
	SFTPB	NM_198843.3		c.529G>A	p.Val177Ile	missense	Exon 6 of 12	NP_942140.3
	SFTPB	NM_001367281.1		c.529G>A	p.Val177Ile	missense	Exon 5 of 9	NP_001354210.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SFTPB	ENST00000519937.7	TSL:1 MANE Select	c.529G>A	p.Val177Ile	missense	Exon 5 of 11	ENSP00000428719.2
	SFTPB	ENST00000393822.7	TSL:1	c.529G>A	p.Val177Ile	missense	Exon 6 of 12	ENSP00000377409.4
	SFTPB	ENST00000409383.7	TSL:1	c.529G>A	p.Val177Ile	missense	Exon 6 of 12	ENSP00000386346.2

Frequencies

GnomAD3 genomes AF: 0.00624 AC: 950 AN: 152168 Hom.: 45 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0554

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00290

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00860

GnomAD2 exomes AF: 0.0158 AC: 3971 AN: 251052 AF XY: 0.0112

Gnomad AFR exome AF: 0.000805

Gnomad AMR exome AF: 0.110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00250

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00930

GnomAD4 exome AF: 0.00369 AC: 5387 AN: 1461822 Hom.: 292 Cov.: 32 AF XY: 0.00303 AC XY: 2207 AN XY: 727212

African (AFR) AF: 0.000986 AC: 33 AN: 33480

American (AMR) AF: 0.106 AC: 4724 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00647 AC: 257 AN: 39700

South Asian (SAS) AF: 0.000638 AC: 55 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.0000935 AC: 104 AN: 1112008

Other (OTH) AF: 0.00353 AC: 213 AN: 60390

GnomAD4 genome AF: 0.00627 AC: 955 AN: 152286 Hom.: 45 Cov.: 32 AF XY: 0.00671 AC XY: 500 AN XY: 74466

African (AFR) AF: 0.00132 AC: 55 AN: 41574

American (AMR) AF: 0.0556 AC: 851 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00291 AC: 15 AN: 5162

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68012

Other (OTH) AF: 0.00851 AC: 18 AN: 2114

Alfa AF: 0.00170 Hom.: 11

Bravo AF: 0.0116

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0116 AC: 1409

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Hereditary pulmonary alveolar proteinosis (1)
-	-	1	not specified (1)
-	-	1	Surfactant metabolism dysfunction, pulmonary, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.2
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.056	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.082
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.058
Sift	Benign	0.40	T
Sift4G	Benign	0.25	T
Polyphen		0.056	B
Vest4		0.023
MPC		0.22
ClinPred		0.0038	T
GERP RS		0.70
Varity_R		0.028
gMVP		0.25
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

Other links and lift over

dbSNP: rs34550459; hg19: chr2-85892782; COSMIC: COSV60893154; COSMIC: COSV60893154;