chr2-32947621-A-ACCG

Variant names:

• chr2-32947621-A-ACCG
• rs538338631
• NM_206943.4:c.316_318dupCCG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_206943.4(LTBP1):​c.316_318dupCCG​(p.Pro106dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,327,122 control chromosomes in the GnomAD database, including 18 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0038 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (17 hom.)
• Consequence: LTBP1 NM_206943.4 conservative_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 0 publications found

Genes affected

LTBP1 (HGNC:6714): (latent transforming growth factor beta binding protein 1) The protein encoded by this gene belongs to the family of latent TGF-beta binding proteins (LTBPs). The secretion and activation of TGF-betas is regulated by their association with latency-associated proteins and with latent TGF-beta binding proteins. The product of this gene targets latent complexes of transforming growth factor beta to the extracellular matrix, where the latent cytokine is subsequently activated by several different mechanisms. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

LTBP1 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal recessive, type 2E

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_206943.4
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00381 (573/150508) while in subpopulation EAS AF = 0.0239 (121/5072). AF 95% confidence interval is 0.0204. There are 1 homozygotes in GnomAd4. There are 282 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_206943.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP1	NM_206943.4	MANE Select	c.316_318dupCCG	p.Pro106dup	conservative_inframe_insertion	Exon 1 of 34	NP_996826.3	Q14766-1
	LTBP1	NM_001394905.1		c.316_318dupCCG	p.Pro106dup	conservative_inframe_insertion	Exon 1 of 34	NP_001381834.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LTBP1	ENST00000404816.7	TSL:5 MANE Select	c.316_318dupCCG	p.Pro106dup	conservative_inframe_insertion	Exon 1 of 34	ENSP00000386043.2	Q14766-1
	LTBP1	ENST00000929169.1		c.316_318dupCCG	p.Pro106dup	conservative_inframe_insertion	Exon 1 of 34	ENSP00000599228.1
	LTBP1	ENST00000954823.1		c.316_318dupCCG	p.Pro106dup	conservative_inframe_insertion	Exon 1 of 34	ENSP00000624882.1

Frequencies

GnomAD3 genomes AF: 0.00379 AC: 570 AN: 150400 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00931

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00139

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0240

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.0000990

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000445

Gnomad OTH AF: 0.00435

GnomAD2 exomes AF: 0.000227 AC: 2 AN: 8816 AF XY: 0.000377

Gnomad AFR exome AF: 0.00575

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00156 AC: 1835 AN: 1176614 Hom.: 17 Cov.: 33 AF XY: 0.00152 AC XY: 871 AN XY: 573438

African (AFR) AF: 0.00850 AC: 197 AN: 23188

American (AMR) AF: 0.00156 AC: 15 AN: 9588

Ashkenazi Jewish (ASJ) AF: 0.000130 AC: 2 AN: 15408

East Asian (EAS) AF: 0.0360 AC: 908 AN: 25204

South Asian (SAS) AF: 0.000842 AC: 38 AN: 45110

European-Finnish (FIN) AF: 0.0000929 AC: 3 AN: 32302

Middle Eastern (MID) AF: 0.00116 AC: 4 AN: 3448

European-Non Finnish (NFE) AF: 0.000561 AC: 547 AN: 974958

Other (OTH) AF: 0.00255 AC: 121 AN: 47408

GnomAD4 genome AF: 0.00381 AC: 573 AN: 150508 Hom.: 1 Cov.: 32 AF XY: 0.00384 AC XY: 282 AN XY: 73522

African (AFR) AF: 0.00938 AC: 387 AN: 41242

American (AMR) AF: 0.00138 AC: 21 AN: 15168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.0239 AC: 121 AN: 5072

South Asian (SAS) AF: 0.000624 AC: 3 AN: 4810

European-Finnish (FIN) AF: 0.0000990 AC: 1 AN: 10100

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000445 AC: 30 AN: 67364

Other (OTH) AF: 0.00431 AC: 9 AN: 2090

Alfa AF: 0.000109 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=83/17	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs538338631; hg19: chr2-33172688; COSMIC: COSV63190092; COSMIC: COSV63190092;