2-178675909-G-T

Variant names:

• chr2-178675909-G-T
• rs74930148
• NM_001267550.2:c.34453+12C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.34453+12C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,604,506 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (13 hom.)
• Consequence: TTN NM_001267550.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: 2.00
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-178675909-G-T is Benign according to our data. Variant chr2-178675909-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00165 (251/152018) while in subpopulation EAS AF = 0.022 (114/5174). AF 95% confidence interval is 0.0188. There are 1 homozygotes in GnomAd4. There are 130 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 13 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	NM_001267550.2	MANE Select	c.34453+12C>A		intron	N/A	NP_001254479.2
	TTN	NM_001256850.1		c.33415+12C>A		intron	N/A	NP_001243779.1
	TTN	NM_133378.4		c.30634+12C>A		intron	N/A	NP_596869.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.34453+12C>A		intron	N/A	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.34453+12C>A		intron	N/A	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.34177+12C>A		intron	N/A	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 253 AN: 151900 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00547

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0220

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000324

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00354 AC: 839 AN: 237242 AF XY: 0.00290

Gnomad AFR exome AF: 0.000270

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.0213

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000244

Gnomad OTH exome AF: 0.00156

GnomAD4 exome AF: 0.00132 AC: 1913 AN: 1452488 Hom.: 13 Cov.: 30 AF XY: 0.00126 AC XY: 912 AN XY: 721494

African (AFR) AF: 0.000180 AC: 6 AN: 33362

American (AMR) AF: 0.0107 AC: 464 AN: 43566

Ashkenazi Jewish (ASJ) AF: 0.0000772 AC: 2 AN: 25922

East Asian (EAS) AF: 0.0251 AC: 991 AN: 39556

South Asian (SAS) AF: 0.00191 AC: 161 AN: 84378

European-Finnish (FIN) AF: 0.000226 AC: 12 AN: 53002

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5750

European-Non Finnish (NFE) AF: 0.000175 AC: 194 AN: 1106910

Other (OTH) AF: 0.00128 AC: 77 AN: 60042

GnomAD4 genome AF: 0.00165 AC: 251 AN: 152018 Hom.: 1 Cov.: 32 AF XY: 0.00175 AC XY: 130 AN XY: 74310

African (AFR) AF: 0.000241 AC: 10 AN: 41516

American (AMR) AF: 0.00546 AC: 83 AN: 15206

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

East Asian (EAS) AF: 0.0220 AC: 114 AN: 5174

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4818

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000324 AC: 22 AN: 67918

Other (OTH) AF: 0.00238 AC: 5 AN: 2102

Alfa AF: 0.00103 Hom.: 1

Bravo AF: 0.00208

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	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;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.4
DANN	Benign	0.47
PhyloP100		2.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74930148; hg19: chr2-179540636;