2-178685560-G-C

Variant names:

• chr2-178685560-G-C
• rs72650029
• NM_001267550.2:c.32350C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001267550.2(TTN):​c.32350C>G​(p.Leu10784Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,613,652 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (7 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:27
• Conservation: PhyloP100: 0.206
• Publications: 8 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038782358).
• BP6: Variant 2-178685560-G-C is Benign according to our data. Variant chr2-178685560-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46864.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 = 0.00427 (651/152284) while in subpopulation AFR AF = 0.0118 (491/41546). AF 95% confidence interval is 0.011. There are 6 homozygotes in GnomAd4. There are 319 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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.32350C>G	p.Leu10784Val	missense	Exon 128 of 363	NP_001254479.2
	TTN	NM_001256850.1		c.31399C>G	p.Leu10467Val	missense	Exon 126 of 313	NP_001243779.1
	TTN	NM_133378.4		c.28618C>G	p.Leu9540Val	missense	Exon 125 of 312	NP_596869.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTN	ENST00000589042.5	TSL:5 MANE Select	c.32350C>G	p.Leu10784Val	missense	Exon 128 of 363	ENSP00000467141.1
	TTN	ENST00000446966.2	TSL:1	c.32350C>G	p.Leu10784Val	missense	Exon 128 of 361	ENSP00000408004.2
	TTN	ENST00000436599.2	TSL:1	c.32074C>G	p.Leu10692Val	missense	Exon 126 of 361	ENSP00000405517.2

Frequencies

GnomAD3 genomes AF: 0.00428 AC: 652 AN: 152164 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0119

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000529

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00207 AC: 515 AN: 248616 AF XY: 0.00192

Gnomad AFR exome AF: 0.0118

Gnomad AMR exome AF: 0.00189

Gnomad ASJ exome AF: 0.0171

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000622

Gnomad OTH exome AF: 0.00282

GnomAD4 exome AF: 0.00114 AC: 1672 AN: 1461368 Hom.: 7 Cov.: 31 AF XY: 0.00115 AC XY: 838 AN XY: 726924

African (AFR) AF: 0.0121 AC: 406 AN: 33464

American (AMR) AF: 0.00195 AC: 87 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 445 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.000244 AC: 21 AN: 86176

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53394

Middle Eastern (MID) AF: 0.00816 AC: 47 AN: 5762

European-Non Finnish (NFE) AF: 0.000440 AC: 489 AN: 1111726

Other (OTH) AF: 0.00292 AC: 176 AN: 60352

GnomAD4 genome AF: 0.00427 AC: 651 AN: 152284 Hom.: 6 Cov.: 32 AF XY: 0.00428 AC XY: 319 AN XY: 74462

African (AFR) AF: 0.0118 AC: 491 AN: 41546

American (AMR) AF: 0.00405 AC: 62 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000529 AC: 36 AN: 68018

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00216 Hom.: 1

Bravo AF: 0.00525

ESP6500AA AF: 0.00973 AC: 37

ESP6500EA AF: 0.00134 AC: 11

ExAC AF: 0.00189 AC: 229

Asia WGS AF: 0.000867 AC: 3 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	not provided (5)
-	-	2	Autosomal recessive limb-girdle muscular dystrophy type 2J (2)
-	-	2	Early-onset myopathy with fatal cardiomyopathy (2)
-	-	2	Myopathy, myofibrillar, 9, with early respiratory failure (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	13
DANN	Benign	0.94
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.21
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.16
Sift	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.24
MVP		0.18
MPC		0.084
ClinPred		0.0030	T
GERP RS		2.0
Mutation Taster		=96/4	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: rs72650029; hg19: chr2-179550287;