chr2-178722403-C-G

Variant names:

• chr2-178722403-C-G
• rs12693166
• NM_001267550.2:c.22384G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001267550.2(TTN):​c.22384G>C​(p.Asp7462His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,612,970 control chromosomes in the GnomAD database, including 24,464 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D7462E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.17 (2496 hom., cov: 32)
  • Exomes 𝑓: 0.16 (21968 hom.)
• Consequence: TTN NM_001267550.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:22
• Conservation: PhyloP100: 7.90
• Publications: 31 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002601415).
• BP6: Variant 2-178722403-C-G is Benign according to our data. Variant chr2-178722403-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 46698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.418 is higher than 0.05.

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.22384G>C	p.Asp7462His	missense	Exon 77 of 363	NP_001254479.2	Q8WZ42-12
	TTN	NM_001256850.1		c.21433G>C	p.Asp7145His	missense	Exon 75 of 313	NP_001243779.1	Q8WZ42-1
	TTN	NM_133378.4		c.18652G>C	p.Asp6218His	missense	Exon 74 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.22384G>C	p.Asp7462His	missense	Exon 77 of 363	ENSP00000467141.1	Q8WZ42-12
	TTN	ENST00000446966.2	TSL:1	c.22384G>C	p.Asp7462His	missense	Exon 77 of 361	ENSP00000408004.2	A0A1B0GXE3
	TTN	ENST00000436599.2	TSL:1	c.22108G>C	p.Asp7370His	missense	Exon 75 of 361	ENSP00000405517.2	A0A0C4DG59

Frequencies

GnomAD3 genomes AF: 0.170 AC: 25821 AN: 151848 Hom.: 2493 Cov.: 32

Gnomad AFR AF: 0.172

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.434

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.0983

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.154

Gnomad OTH AF: 0.169

GnomAD2 exomes AF: 0.179 AC: 44246 AN: 247828 AF XY: 0.180

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.174

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.431

Gnomad FIN exome AF: 0.0959

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.164 AC: 239397 AN: 1461004 Hom.: 21968 Cov.: 34 AF XY: 0.165 AC XY: 120005 AN XY: 726762

African (AFR) AF: 0.173 AC: 5769 AN: 33440

American (AMR) AF: 0.175 AC: 7825 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 3238 AN: 26116

East Asian (EAS) AF: 0.444 AC: 17621 AN: 39670

South Asian (SAS) AF: 0.220 AC: 18965 AN: 86212

European-Finnish (FIN) AF: 0.0936 AC: 4993 AN: 53370

Middle Eastern (MID) AF: 0.199 AC: 1144 AN: 5762

European-Non Finnish (NFE) AF: 0.153 AC: 169496 AN: 1111436

Other (OTH) AF: 0.171 AC: 10346 AN: 60340

GnomAD4 genome AF: 0.170 AC: 25836 AN: 151966 Hom.: 2496 Cov.: 32 AF XY: 0.171 AC XY: 12696 AN XY: 74268

African (AFR) AF: 0.171 AC: 7110 AN: 41474

American (AMR) AF: 0.173 AC: 2638 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 437 AN: 3468

East Asian (EAS) AF: 0.433 AC: 2226 AN: 5136

South Asian (SAS) AF: 0.225 AC: 1081 AN: 4812

European-Finnish (FIN) AF: 0.0983 AC: 1040 AN: 10584

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.154 AC: 10470 AN: 67928

Other (OTH) AF: 0.173 AC: 365 AN: 2108

Alfa AF: 0.152 Hom.: 1642

Bravo AF: 0.178

TwinsUK AF: 0.149 AC: 554

ALSPAC AF: 0.155 AC: 596

ESP6500AA AF: 0.168 AC: 623

ESP6500EA AF: 0.152 AC: 1252

ExAC AF: 0.178 AC: 21487

Asia WGS AF: 0.330 AC: 1150 AN: 3478

EpiCase AF: 0.153

EpiControl AF: 0.160

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (9)
-	-	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	not provided (2)
-	-	2	Tibial muscular dystrophy (2)
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2J;C1858763:Dilated cardiomyopathy 1G (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Dilated cardiomyopathy 1G (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Benign	0.91
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
PhyloP100		7.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.53
Sift	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.11
MPC		0.50
ClinPred		0.017	T
GERP RS		6.2
Mutation Taster		=50/50	polymorphism (auto)

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: rs12693166; hg19: chr2-179587130; COSMIC: COSV59895347; COSMIC: COSV59895347;