rs190209925

Variant names:

• chr2-178675703-C-A
• rs190209925
• NM_001267550.2:c.34505G>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001267550.2(TTN):​c.34505G>T​(p.Gly11502Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000397 in 1,424,930 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 10/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.0770
• Publications: 0 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076554716).
• BP6: Variant 2-178675703-C-A is Benign according to our data. Variant chr2-178675703-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 405101.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00193 (293/151894) while in subpopulation AFR AF = 0.00692 (287/41450). AF 95% confidence interval is 0.00627. There are 1 homozygotes in GnomAd4. There are 133 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.34505G>T	p.Gly11502Val	missense	Exon 149 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.33415+218G>T		intron	N/A	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.30634+218G>T		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.34505G>T	p.Gly11502Val	missense	Exon 149 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.34505G>T	p.Gly11502Val	missense	Exon 149 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.34229G>T	p.Gly11410Val	missense	Exon 147 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 294 AN: 151776 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00697

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000667 AC: 40 AN: 59938 AF XY: 0.000559

Gnomad AFR exome AF: 0.00639

Gnomad AMR exome AF: 0.000394

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000505

GnomAD4 exome AF: 0.000214 AC: 272 AN: 1273036 Hom.: 0 Cov.: 30 AF XY: 0.000175 AC XY: 108 AN XY: 617920

African (AFR) AF: 0.00826 AC: 232 AN: 28086

American (AMR) AF: 0.000570 AC: 11 AN: 19286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18902

East Asian (EAS) AF: 0.00 AC: 0 AN: 34590

South Asian (SAS) AF: 0.00 AC: 0 AN: 55952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3616

European-Non Finnish (NFE) AF: 0.00000388 AC: 4 AN: 1030950

Other (OTH) AF: 0.000471 AC: 25 AN: 53044

GnomAD4 genome AF: 0.00193 AC: 293 AN: 151894 Hom.: 1 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74268

African (AFR) AF: 0.00692 AC: 287 AN: 41450

American (AMR) AF: 0.000131 AC: 2 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67878

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.00162 Hom.: 0

Bravo AF: 0.00224

ExAC AF: 0.000336 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	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	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	not specified (1)
-	-	1	Tibial muscular dystrophy (1)
-	-	1	TTN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.58
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.26	T
M_CAP	Benign	0.0050	T
MetaRNN	Benign	0.0077	T
PhyloP100		-0.077
Vest4		0.20
MVP		0.84
GERP RS		-0.73
Mutation Taster		=95/5	polymorphism

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: rs190209925; hg19: chr2-179540430;