2-178702075-TAA-TAAA

Variant names:

• chr2-178702075-T-TA
• rs397517532
• NM_001267550.2:c.30512-10dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.30512-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0536 in 1,473,500 control chromosomes in the GnomAD database, including 2,713 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (1111 hom., cov: 31)
  • Exomes 𝑓: 0.049 (1602 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 2.83
• Publications: 1 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 -16 ACMG points.

• BP6: Variant 2-178702075-T-TA is Benign according to our data. Variant chr2-178702075-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46838.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

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.30512-10dupT		intron	N/A	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.29561-10dupT		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.26780-10dupT		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.30512-10_30512-9insT		intron	N/A	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.30512-10_30512-9insT		intron	N/A	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.30236-10_30236-9insT		intron	N/A	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.0918 AC: 13753 AN: 149800 Hom.: 1097 Cov.: 31

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0322

Gnomad EAS AF: 0.0335

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.0603

Gnomad MID AF: 0.0637

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0722

GnomAD2 exomes AF: 0.107 AC: 18502 AN: 172130 AF XY: 0.105

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.243

Gnomad ASJ exome AF: 0.0490

Gnomad EAS exome AF: 0.0430

Gnomad FIN exome AF: 0.0724

Gnomad NFE exome AF: 0.0399

Gnomad OTH exome AF: 0.0868

GnomAD4 exome AF: 0.0492 AC: 65135 AN: 1323594 Hom.: 1602 Cov.: 32 AF XY: 0.0513 AC XY: 33752 AN XY: 657808

African (AFR) AF: 0.197 AC: 6018 AN: 30612

American (AMR) AF: 0.191 AC: 7713 AN: 40320

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 891 AN: 23252

East Asian (EAS) AF: 0.0292 AC: 1053 AN: 36060

South Asian (SAS) AF: 0.167 AC: 12945 AN: 77450

European-Finnish (FIN) AF: 0.0626 AC: 3052 AN: 48784

Middle Eastern (MID) AF: 0.0556 AC: 297 AN: 5340

European-Non Finnish (NFE) AF: 0.0297 AC: 29908 AN: 1006970

Other (OTH) AF: 0.0594 AC: 3258 AN: 54806

GnomAD4 genome AF: 0.0922 AC: 13815 AN: 149906 Hom.: 1111 Cov.: 31 AF XY: 0.0975 AC XY: 7140 AN XY: 73196

African (AFR) AF: 0.190 AC: 7777 AN: 40914

American (AMR) AF: 0.154 AC: 2319 AN: 15078

Ashkenazi Jewish (ASJ) AF: 0.0322 AC: 111 AN: 3446

East Asian (EAS) AF: 0.0340 AC: 174 AN: 5120

South Asian (SAS) AF: 0.170 AC: 804 AN: 4720

European-Finnish (FIN) AF: 0.0603 AC: 609 AN: 10104

Middle Eastern (MID) AF: 0.0582 AC: 17 AN: 292

European-Non Finnish (NFE) AF: 0.0270 AC: 1817 AN: 67264

Other (OTH) AF: 0.0719 AC: 148 AN: 2058

Alfa AF: 0.0280 Hom.: 12

Bravo AF: 0.0987

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	4	not provided (4)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J (1)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Dilated Cardiomyopathy, Dominant (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
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: rs397517532; hg19: chr2-179566802;