chr2-178630241-G-A

Variant names:

• chr2-178630241-G-A
• rs192766485
• NM_001267550.2:c.44281C>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.44281C>T​(p.Pro14761Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00116 in 1,612,582 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts 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. P14761P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00082 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: TTN NM_001267550.2 missense
• Scores: Splicing: ADA: 0.9717
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:18
• Conservation: PhyloP100: 7.17
• Publications: 9 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=0.044150203).
• BP6: Variant 2-178630241-G-A is Benign according to our data. Variant chr2-178630241-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178217.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000823 (125/151928) while in subpopulation AMR AF = 0.0023 (35/15224). AF 95% confidence interval is 0.0017. There are 0 homozygotes in GnomAd4. There are 61 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 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.44281C>T	p.Pro14761Ser	missense	Exon 239 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.39358C>T	p.Pro13120Ser	missense	Exon 189 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.36577C>T	p.Pro12193Ser	missense	Exon 188 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.44281C>T	p.Pro14761Ser	missense	Exon 239 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.44125C>T	p.Pro14709Ser	missense	Exon 237 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.44005C>T	p.Pro14669Ser	missense	Exon 237 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.000823 AC: 125 AN: 151810 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00230

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: 0.00116

Gnomad OTH AF: 0.000480

GnomAD2 exomes AF: 0.000657 AC: 163 AN: 248262 AF XY: 0.000661

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000697

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00112

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00120 AC: 1750 AN: 1460654 Hom.: 4 Cov.: 31 AF XY: 0.00111 AC XY: 808 AN XY: 726580

African (AFR) AF: 0.000299 AC: 10 AN: 33420

American (AMR) AF: 0.000672 AC: 30 AN: 44660

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86124

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00150 AC: 1668 AN: 1111284

Other (OTH) AF: 0.000663 AC: 40 AN: 60316

GnomAD4 genome AF: 0.000823 AC: 125 AN: 151928 Hom.: 0 Cov.: 32 AF XY: 0.000822 AC XY: 61 AN XY: 74216

African (AFR) AF: 0.000241 AC: 10 AN: 41470

American (AMR) AF: 0.00230 AC: 35 AN: 15224

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10542

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

European-Non Finnish (NFE) AF: 0.00116 AC: 79 AN: 67962

Other (OTH) AF: 0.000475 AC: 1 AN: 2106

Alfa AF: 0.000978 Hom.: 9

Bravo AF: 0.000990

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000612 AC: 5

ExAC AF: 0.000546 AC: 66

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	9	not provided (12)
-	-	4	not specified (4)
-	2	-	Dilated cardiomyopathy 1G (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	Cardiovascular phenotype (1)
-	1	-	Early-onset myopathy with fatal cardiomyopathy (1)
-	1	-	Hypertrophic cardiomyopathy 9 (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	Benign	0.29
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Benign	0.94
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.044	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.2
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.28
Sift	Benign	0.22	T
Polyphen		0.84	P
Vest4		0.51
MVP		0.33
MPC		0.11
ClinPred		0.055	T
GERP RS		6.0
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.65
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: rs192766485; hg19: chr2-179494968; COSMIC: COSV60108913; COSMIC: COSV60108913;