rs199632397

Variant names:

• chr2-178529076-C-G
• rs199632397
• NM_001267550.2:c.106675G>C
• TTN p.Glu35559Gln

Your query was ambiguous. Multiple possible variants found:

• chr2-178529076-C-G
• chr2-178529076-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001267550.2(TTN):​c.106675G>C​(p.Glu35559Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,613,336 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (3 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:13
• Conservation: PhyloP100: 1.61
• Publications: 4 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]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021069646).
• BP6: Variant 2-178529076-C-G is Benign according to our data. Variant chr2-178529076-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 192135.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000379 (554/1461086) while in subpopulation MID AF = 0.00312 (18/5766). AF 95% confidence interval is 0.00202. There are 3 homozygotes in GnomAdExome4. There are 294 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 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.106675G>C	p.Glu35559Gln	missense	Exon 360 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.101752G>C	p.Glu33918Gln	missense	Exon 310 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.98971G>C	p.Glu32991Gln	missense	Exon 309 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.106675G>C	p.Glu35559Gln	missense	Exon 360 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.106519G>C	p.Glu35507Gln	missense	Exon 358 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.106399G>C	p.Glu35467Gln	missense	Exon 358 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152132 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000426 AC: 106 AN: 248704 AF XY: 0.000504

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.000796

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.000470

Gnomad OTH exome AF: 0.000830

GnomAD4 exome AF: 0.000379 AC: 554 AN: 1461086 Hom.: 3 Cov.: 32 AF XY: 0.000405 AC XY: 294 AN XY: 726800

African (AFR) AF: 0.000120 AC: 4 AN: 33402

American (AMR) AF: 0.0000448 AC: 2 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00115 AC: 99 AN: 86196

European-Finnish (FIN) AF: 0.0000938 AC: 5 AN: 53304

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5766

European-Non Finnish (NFE) AF: 0.000332 AC: 369 AN: 1111640

Other (OTH) AF: 0.000630 AC: 38 AN: 60322

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152250 Hom.: 0 Cov.: 33 AF XY: 0.000296 AC XY: 22 AN XY: 74412

African (AFR) AF: 0.0000241 AC: 1 AN: 41556

American (AMR) AF: 0.000131 AC: 2 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68010

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000409 Hom.: 0

Bravo AF: 0.000249

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	1	3	not specified (4)
-	1	1	Cardiovascular phenotype (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	Cardiomyopathy (1)
-	1	-	Dilated cardiomyopathy 1G (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)
-	1	-	TTN-related disorder (1)
-	1	-	TTN-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.85
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.55	N
PhyloP100		1.6
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.098
Sift	Benign	0.065	T
Mutation Taster		=93/7	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs199632397;

hg19: chr2-179393803;