rs189966800

Variant names:

• chr2-178671134-T-G
• rs189966800
• NM_001267550.2:c.35264A>C

Your query was ambiguous. Multiple possible variants found:

• chr2-178671134-T-G
• chr2-178671134-T-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_001267550.2(TTN):​c.35264A>C​(p.Lys11755Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000342 in 1,604,464 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K11755N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00019 (0 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:16
• Conservation: PhyloP100: 3.64
• Publications: 3 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.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006884694).
• BP6: Variant 2-178671134-T-G is Benign according to our data. Variant chr2-178671134-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46914.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00183 (278/151954) while in subpopulation AFR AF = 0.00628 (261/41536). AF 95% confidence interval is 0.00566. There are 1 homozygotes in GnomAd4. There are 120 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.35264A>C	p.Lys11755Thr	missense	Exon 156 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.34142A>C	p.Lys11381Thr	missense	Exon 152 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.31361A>C	p.Lys10454Thr	missense	Exon 151 of 312	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.35264A>C	p.Lys11755Thr	missense	Exon 156 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.35264A>C	p.Lys11755Thr	missense	Exon 156 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.34988A>C	p.Lys11663Thr	missense	Exon 154 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 278 AN: 151836 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00630

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000724

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: 0.0000295

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000437 AC: 104 AN: 238212 AF XY: 0.000347

Gnomad AFR exome AF: 0.00623

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000469

Gnomad NFE exome AF: 0.00000914

Gnomad OTH exome AF: 0.000178

GnomAD4 exome AF: 0.000186 AC: 270 AN: 1452510 Hom.: 0 Cov.: 30 AF XY: 0.000154 AC XY: 111 AN XY: 722444

African (AFR) AF: 0.00682 AC: 223 AN: 32720

American (AMR) AF: 0.000394 AC: 17 AN: 43198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.00 AC: 0 AN: 39132

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84354

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53262

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5706

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1108260

Other (OTH) AF: 0.000384 AC: 23 AN: 59926

GnomAD4 genome AF: 0.00183 AC: 278 AN: 151954 Hom.: 1 Cov.: 32 AF XY: 0.00162 AC XY: 120 AN XY: 74278

African (AFR) AF: 0.00628 AC: 261 AN: 41536

American (AMR) AF: 0.000723 AC: 11 AN: 15220

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67798

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000433 Hom.: 9

Bravo AF: 0.00233

ESP6500AA AF: 0.00501 AC: 18

ESP6500EA AF: 0.000123 AC: 1

ExAC AF: 0.000613 AC: 74

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	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	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	1.0
Eigen	Benign	0.099
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-0.78	T
PhyloP100		3.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.27
Sift	Pathogenic	0.0	D
Polyphen		0.74	P
Vest4		0.36
MVP		0.45
MPC		0.16
ClinPred		0.13	T
GERP RS		4.8
Mutation Taster		=85/15	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: rs189966800; hg19: chr2-179535861;