chr2-178685261-G-A

Variant names:

• chr2-178685261-G-A
• rs146400809
• NM_001267550.2:c.32462C>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.32462C>T​(p.Pro10821Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000652 in 1,547,046 control chromosomes in the GnomAD database, including 2 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). Synonymous variant affecting the same amino acid position (i.e. P10821P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (2 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:12
• Conservation: PhyloP100: 2.33
• Publications: 13 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=0.0057966113).
• BP6: Variant 2-178685261-G-A is Benign according to our data. Variant chr2-178685261-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 46867.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00104 (158/152158) while in subpopulation EAS AF = 0.00734 (38/5178). AF 95% confidence interval is 0.0055. There are 0 homozygotes in GnomAd4. There are 111 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.32462C>T	p.Pro10821Leu	missense	Exon 129 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.31511C>T	p.Pro10504Leu	missense	Exon 127 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.28730C>T	p.Pro9577Leu	missense	Exon 126 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.32462C>T	p.Pro10821Leu	missense	Exon 129 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.32462C>T	p.Pro10821Leu	missense	Exon 129 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.32186C>T	p.Pro10729Leu	missense	Exon 127 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 153 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00732

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.00557

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00113 AC: 175 AN: 154258 AF XY: 0.00108

Gnomad AFR exome AF: 0.000360

Gnomad AMR exome AF: 0.0000411

Gnomad ASJ exome AF: 0.000949

Gnomad EAS exome AF: 0.00373

Gnomad FIN exome AF: 0.00483

Gnomad NFE exome AF: 0.000393

Gnomad OTH exome AF: 0.000929

GnomAD4 exome AF: 0.000610 AC: 851 AN: 1394888 Hom.: 2 Cov.: 31 AF XY: 0.000615 AC XY: 423 AN XY: 687674

African (AFR) AF: 0.000192 AC: 6 AN: 31236

American (AMR) AF: 0.0000570 AC: 2 AN: 35106

Ashkenazi Jewish (ASJ) AF: 0.00124 AC: 31 AN: 25058

East Asian (EAS) AF: 0.00428 AC: 154 AN: 36000

South Asian (SAS) AF: 0.00100 AC: 77 AN: 77028

European-Finnish (FIN) AF: 0.00570 AC: 281 AN: 49300

Middle Eastern (MID) AF: 0.000365 AC: 2 AN: 5484

European-Non Finnish (NFE) AF: 0.000210 AC: 226 AN: 1077902

Other (OTH) AF: 0.00125 AC: 72 AN: 57774

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.00149 AC XY: 111 AN XY: 74374

African (AFR) AF: 0.000481 AC: 20 AN: 41544

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00734 AC: 38 AN: 5178

South Asian (SAS) AF: 0.00208 AC: 10 AN: 4814

European-Finnish (FIN) AF: 0.00557 AC: 59 AN: 10584

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

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67970

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000662 Hom.: 3

Bravo AF: 0.000559

ESP6500AA AF: 0.000285 AC: 1

ESP6500EA AF: 0.000126 AC: 1

ExAC AF: 0.000648 AC: 69

Asia WGS AF: 0.00809 AC: 28 AN: 3474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	3	not provided (3)
-	-	1	Abnormality of neuronal migration (1)
-	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	Hypertrophic cardiomyopathy (1)
-	-	1	Myopathy, myofibrillar, 9, with early respiratory failure (1)
-	-	1	Tibial muscular dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	20
DANN	Benign	0.88
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.0058	T
MetaSVM	Uncertain	-0.23	T
PhyloP100		2.3
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.22
Sift	Benign	0.032	D
Polyphen		1.0	D
Vest4		0.24
MVP		0.64
MPC		0.42
ClinPred		0.053	T
GERP RS		6.1
Mutation Taster		=77/23	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: rs146400809; hg19: chr2-179549988; COSMIC: COSV105911366;