rs140640738

Variant names:

• chr2-178675085-T-G
• rs140640738
• NM_001267550.2:c.34566A>C

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.34566A>C​(p.Glu11522Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00204 in 1,561,344 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 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. E11522G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (39 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:21
• Conservation: PhyloP100: 0.842
• Publications: 7 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0028508902).
• BP6: Variant 2-178675085-T-G is Benign according to our data. Variant chr2-178675085-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46904.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00182 (277/152010) while in subpopulation SAS AF = 0.0239 (115/4812). AF 95% confidence interval is 0.0204. There are 5 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 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.34566A>C	p.Glu11522Asp	missense	Exon 150 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.33444A>C	p.Glu11148Asp	missense	Exon 146 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.30663A>C	p.Glu10221Asp	missense	Exon 145 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.34566A>C	p.Glu11522Asp	missense	Exon 150 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.34566A>C	p.Glu11522Asp	missense	Exon 150 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.34290A>C	p.Glu11430Asp	missense	Exon 148 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00180 AC: 274 AN: 151892 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.000870

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0233

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00345 AC: 707 AN: 205174 AF XY: 0.00440

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000787

Gnomad ASJ exome AF: 0.000991

Gnomad EAS exome AF: 0.0000764

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00317

GnomAD4 exome AF: 0.00207 AC: 2914 AN: 1409334 Hom.: 39 Cov.: 28 AF XY: 0.00263 AC XY: 1836 AN XY: 699300

African (AFR) AF: 0.000502 AC: 15 AN: 29854

American (AMR) AF: 0.000655 AC: 23 AN: 35092

Ashkenazi Jewish (ASJ) AF: 0.000875 AC: 22 AN: 25140

East Asian (EAS) AF: 0.000197 AC: 7 AN: 35496

South Asian (SAS) AF: 0.0204 AC: 1532 AN: 75250

European-Finnish (FIN) AF: 0.0000756 AC: 4 AN: 52888

Middle Eastern (MID) AF: 0.00389 AC: 22 AN: 5660

European-Non Finnish (NFE) AF: 0.00103 AC: 1127 AN: 1091632

Other (OTH) AF: 0.00278 AC: 162 AN: 58322

GnomAD4 genome AF: 0.00182 AC: 277 AN: 152010 Hom.: 5 Cov.: 32 AF XY: 0.00209 AC XY: 155 AN XY: 74328

African (AFR) AF: 0.000313 AC: 13 AN: 41522

American (AMR) AF: 0.00184 AC: 28 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.000870 AC: 3 AN: 3448

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

South Asian (SAS) AF: 0.0239 AC: 115 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00168 AC: 114 AN: 67904

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

Alfa AF: 0.00154 Hom.: 1

Bravo AF: 0.00110

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000818 AC: 3

ESP6500EA AF: 0.00184 AC: 15

ExAC AF: 0.00429 AC: 518

Asia WGS AF: 0.0130 AC: 44 AN: 3474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	1	5	not provided (6)
-	-	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	Primary dilated cardiomyopathy (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.79
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.40	T
MetaRNN	Benign	0.0029	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.84
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Benign	0.23	T
Polyphen		0.26	B
Vest4		0.16
MutPred		0.10		Loss of ubiquitination at K11144 (P = 0.1343)
MVP		0.32
MPC		0.092
ClinPred		0.026	T
GERP RS		3.3
Mutation Taster		=99/1	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: rs140640738; hg19: chr2-179539812;