NM_001267550.2:c.40408+7_40408+10dupAATG

Variant names:

• chr2-178645909-G-GCATT
• rs397517560
• NM_001267550.2:c.40408+7_40408+10dupAATG

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_001267550.2(TTN):​c.40408+7_40408+10dupAATG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,515,786 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00030 (7 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8
• Conservation: PhyloP100: -0.169
• Publications: 2 publications found

Genes affected

TTN (HGNC:12403): (titin) This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma. [provided by RefSeq, Feb 2012]

TTN-AS1 (HGNC:44124): (TTN antisense RNA 1) This gene encodes a non-coding RNA transcribed from the opposite strand to the titin gene. [provided by RefSeq, Aug 2016]

LOC124906100 (HGNC:):

ACMG classification

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

• BP6: Variant 2-178645909-G-GCATT is Benign according to our data. Variant chr2-178645909-G-GCATT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46934.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000152 (23/151564) while in subpopulation SAS AF = 0.0046 (22/4786). AF 95% confidence interval is 0.00311. There are 0 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 7 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001267550.2. 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
	TTN	NM_001267550.2	MANE Select	c.40408+7_40408+10dupAATG		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.35485+7_35485+10dupAATG		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.32704+7_32704+10dupAATG		intron	N/A	NP_596869.4	Q8WZ42-11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.40408+7_40408+10dupAATG		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.40408+7_40408+10dupAATG		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.40132+7_40132+10dupAATG		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 23 AN: 151444 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00459

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000689 AC: 111 AN: 161046 AF XY: 0.000926

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000714

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000301 AC: 410 AN: 1364222 Hom.: 7 Cov.: 27 AF XY: 0.000464 AC XY: 313 AN XY: 674524

African (AFR) AF: 0.00 AC: 0 AN: 29880

American (AMR) AF: 0.00 AC: 0 AN: 32428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24322

East Asian (EAS) AF: 0.00 AC: 0 AN: 34474

South Asian (SAS) AF: 0.00528 AC: 382 AN: 72406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50600

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5552

European-Non Finnish (NFE) AF: 0.00000378 AC: 4 AN: 1058052

Other (OTH) AF: 0.000407 AC: 23 AN: 56508

GnomAD4 genome AF: 0.000152 AC: 23 AN: 151564 Hom.: 0 Cov.: 31 AF XY: 0.000216 AC XY: 16 AN XY: 73988

African (AFR) AF: 0.00 AC: 0 AN: 41388

American (AMR) AF: 0.00 AC: 0 AN: 15160

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5108

South Asian (SAS) AF: 0.00460 AC: 22 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67822

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.00404 AC: 14 AN: 3476

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiomyopathy (1)
-	1	-	Dilated Cardiomyopathy, Dominant (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy (1)
-	1	-	Limb-girdle muscular dystrophy, recessive (1)
-	1	-	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	1	-	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.17
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs397517560; hg19: chr2-179510636;